Dimensionless physical constant At the present time, the values of the dimensionless physical constants cannot be calculated; they are determined only by physical measurement. What is the minimum number of dimensionless physical constants from which all other dimensionless physical constants can be derived? Are dimensionful physical constants necessary at all?
Fine-tuned Universe The values of the fundamental physical constants are in a narrow range necessary to support carbon-based life. Is this because there exist other universes with different constants, or are our universe’s constants the result of chance, or some other factor or process?
Dark energy What is the cause of the observed accelerated expansion (de Sitter phase) of the universe? Why is the energy density of the dark energy component of the same magnitude as the density of matter at present when the two evolve quite differently over time; could it be simply that we are observing at exactly the right time? Is dark energy a pure cosmological constant or are models of quintessence such as phantom energy applicable?
Dark flow Is a non-spherically symmetric gravitational pull from outside the observable universe responsible for some of the observed motion of large objects such as galactic clusters in the universe?
Ecliptic alignment of CMB anisotropy Some large features of the microwave sky at distances of over 13 billion light years appear to be aligned with both the motion and orientation of the solar system. Is this due to systematic errors in processing, contamination of results by local effects, or an unexplained violation of the Copernican principle?
Shape of the universe What is the 3-manifold of comoving space, i.e. of a comoving spatial section of the universe, informally called the "shape" of the universe? Neither the curvature nor the topology is presently known, though the curvature is known to be "close" to zero on observable scales. The cosmic inflation hypothesis suggests that the shape of the universe may be unmeasurable, but, since 2003, Jean-Pierre Luminet, et al., and other groups have suggested that the shape of the universe may be the Poincaré dodecahedral space. Is the shape unmeasurable; the Poincaré space; or another 3-manifold?
Quantum gravity Can quantum mechanics and general relativity be realized as a fully consistent theory (perhaps as a quantum field theory)? Is spacetime fundamentally continuous or discrete? Would a consistent theory involve a force mediated by a hypothetical graviton, or be a product of a discrete structure of spacetime itself (as in loop quantum gravity)? Are there deviations from the predictions of general relativity at very small or very large scales or in other extreme circumstances that flow from a quantum gravity theory?
Black holes, black hole information paradox, and black hole radiation Do black holes produce thermal radiation, as expected on theoretical grounds? Does this radiation contain information about their inner structure, as suggested by gauge–gravity duality, or not, as implied by Hawking's original calculation? If not, and black holes can evaporate away, what happens to the information stored in them (since quantum mechanics does not provide for the destruction of information)? Or does the radiation stop at some point leaving black hole remnants? Is there another way to probe their internal structure somehow, if such a structure even exists?
Extra dimensions Does nature have more than four spacetime dimensions? If so, what is their size? Are dimensions a fundamental property of the universe or an emergent result of other physical laws? Can we experimentally observe evidence of higher spatial dimensions?
Locality Are there non-local phenomena in quantum physics? If they exist, are non-local phenomena limited to the entanglement revealed in the violations of the Bell inequalities, or can information and conserved quantities also move in a non-local way? Under what circumstances are non-local phenomena observed? What does the existence or absence of non-local phenomena imply about the fundamental structure of spacetime? How does this relate to quantum entanglement? How does this elucidate the proper interpretation of the fundamental nature of quantum physics?
Planck particle The Planck mass plays an important role in parts of mathematical physics. A series of researchers have suggested the existence of a fundamental particle with mass equal to or close to that of the Planck mass. The Planck mass is however enormous compared to any detected particle even compared to the Higgs particle. While working at the Rutherford Laboratory, Lloyd Motz suggested that such a particle with Planck mass likely had existed but that most of its mass had radiated away. Others have suggested particles with close to the Planck mass are micro black holes. It is still an unsolved problem if there exist or even have existed a particle with close to the Planck mass. This is indirectly related to the hierarchy problem.
Proton decayand spin crisis Is the proton fundamentally stable? Or does it decay with a finite lifetime as predicted by some extensions to the standard model? How do the quarks and gluons carry the spin of protons?
Anomalous magnetic dipole moment Why is the experimentally measured value of the muon's anomalous magnetic dipole moment ("muon g−2") significantly different from the theoretically predicted value of that physical constant?
Pentaquarks and other exotic hadrons What combinations of quarks are possible? Why were pentaquarks so difficult to discover? Are they a tightly-bound system of five elementary particles, or a more weakly-bound pairing of a baryon and a meson?
Solar cycle How does the Sun generate its periodically reversing large-scale magnetic field? How do other solar-like stars generate their magnetic fields, and what are the similarities and differences between stellar activity cycles and that of the Sun? What caused the Maunder Minimum and other grand minima, and how does the solar cycle recover from a minima state?
Diffuse interstellar bands What is responsible for the numerous interstellar absorption lines detected in astronomical spectra? Are they molecular in origin, and if so which molecules are responsible for them? How do they form?
Supermassive black holes What is the origin of the M-sigma relation between supermassive black hole mass and galaxy velocity dispersion? How did the most distant quasars grow their supermassive black holes up to 1010 solar masses so early in the history of the universe?
Kuiper cliff Why does the number of objects in the Solar System's Kuiper belt fall off rapidly and unexpectedly beyond a radius of 50 astronomical units?
Flyby anomaly Why is the observed energy of satellites flying by Earth sometimes different by a minute amount from the value predicted by theory?
Galaxy rotation problem Is dark matter responsible for differences in observed and theoretical speed of stars revolving around the centre of galaxies, or is it something else?
Supernovae What is the exact mechanism by which an implosion of a dying star becomes an explosion?
Large-scale anisotropy Is the universe at very large scales anisotropic, making the cosmological principle an invalid assumption? The number count and intensity dipole anisotropy in radio, NRAO VLA Sky Survey (NVSS) catalogue is inconsistent with the local motion as derived from cosmic microwave background and indicate an intrinsic dipole anisotropy. The same NVSS radio data also shows an intrinsic dipole in polarization density and degree of polarization in the same direction as in number count and intensity. There are other several observation revealing large-scale anisotropy. The optical polarization from quasars shows polarization alignment over a very large scale of Gpc.The cosmic-microwave-background data shows several features of anisotropy, which are not consistent with the Big Bang model.
Space roar Why is space roar six times louder than expected? What is the source of space roar?
Age–metallicity relation in the Galactic disk Is there a universal age–metallicity relation (AMR) in the Galactic disk (both "thin" and "thick" parts of the disk)? Although in the local (primarily thin) disk of the Milky Way there is no evidence of a strong AMR, a sample of 229 nearby "thick" disk stars has been used to investigate the existence of an age–metallicity relation in the Galactic thick disk, and indicate that there is an age–metallicity relation present in the thick disk. Stellar ages from asteroseismology confirm the lack of any strong age-metallicity relation in the Galactic disc.
The injection problem Fermi acceleration is thought to be the primary mechanism that accelerates astrophysical particles to high energy. However, it is unclear what mechanism causes those particles to initially have energies high enough for Fermi acceleration to work on them. Fast radio bursts Transient radio pulses lasting only a few milliseconds, from emission regions thought to be no larger than a few hundred kilometres, and estimated to occur several hundred times a day. While several theories have been proposed, there is no generally accepted explanation for them. They may come from cosmological distances, but there is no consensus on this, either.
Amorphous solids What is the nature of the glass transition between a fluid or regular solid and a glassy phase? What are the physical processes giving rise to the general properties of glasses and the glass transition?
Plasma physics and fusion power Fusion energy may potentially provide power from abundant resource (e.g. hydrogen) without the type of radioactive waste that fission energy currently produces. However, can ionized gases (plasma) be confined long enough and at a high enough temperature to create fusion power? What is the physical origin of H-mode?
Stochasticity and robustness to noise in gene expression How do genes govern our body, withstanding different external pressures and internal stochasticity? Certain models exist for genetic processes, but we are far from understanding the whole picture, in particular in development where gene expression must be tightly regulated.
Quantitative study of the immune system What are the quantitative properties of immune responses? What are the basic building blocks of immune system networks?
Existence of time crystals (2012–2016) In 2016, the idea of time-crystals was proposed by two groups independently Khemani et.al.  and Else et.al. Both of these groups showed that in small systems which are disordered and periodic in time, one can observe the phenomenon of time crystals. Norman Yao et.al. extended the calculations for a model (which has the same qualitative features) in the laboratory environment. This was then used by two teams, a group led by Christopher Monroe at the University of Maryland and a group led by Mikhail Lukin at Harvard university, who were both able to show evidence for a time crystals in the lab-setting, showing that for short times the systems exhibited the dynamics similar to the predicted one. However, at longer times, the dynamics deviated from an ideal time-crystalline behavior. These short time dynamics were taken as the time-crystalline phenomena and the resulting experiments have been published in Nature. However, a demonstration of such a phenomenon and its survival in the limit of many-particles as well as for longer times remains an open question, in both theory and experiment. Existence of gravitational waves (1916–2016) On 11 February 2016, the Advanced LIGO team announced that they had directly detected gravitational waves from a pair of black holes merging, which was also the first detection of a stellar binary black hole.
Photon underproduction crisis (2014–2015) This problem was resolved by Khaire and Srianand. They show that a factor 2 to 5 times large metagalactic photoionization rate can be easily obtained using updated quasar and galaxy observations. Recent observations of quasars indicate that the quasar contribution to ultraviolet photons is a factor of 2 larger than previous estimates. The revised galaxy contribution is a factor of 3 larger. These together solve the crisis.
Existence of ball lightning (1638–2014) In January 2014, scientists from Northwest Normal University in Lanzhou, China, published the results of recordings made in July 2012 of the optical spectrum of what was thought to be natural ball lightning made during the study of ordinary cloud–ground lightning on China's Qinghai Plateau. At a distance of 900 m (3,000 ft), a total of 1.3 seconds of digital video of the ball lightning and its spectrum was made, from the formation of the ball lightning after the ordinary lightning struck the ground, up to the optical decay of the phenomenon. The recorded ball lightning is believed to be vaporized soil elements that then rapidly oxidize in the atmosphere. The nature of the true theory is still not clear. Higgs boson and electroweak symmetry breaking (1963–2012) The mechanism responsible for breaking the electroweak gauge symmetry, giving mass to the W and Z bosons, was solved with the discovery of the Higgs boson of the Standard Model, with the expected couplings to the weak bosons. No evidence of a strong dynamics solution, as proposed by technicolor, has been observed.
Hipparcos anomaly (1997–2012) The High Precision Parallax Collecting Satellite (Hipparcos) measured the parallax of the Pleiades and determined a distance of 385 light years. This was significantly different from other measurements made by means of actual to apparent brightness measurement or absolute magnitude. The anomaly was due to the use of a weighted mean when there is a correlation between distances and distance errors for stars in clusters. It is resolved by using an unweighted mean. There is no systematic bias in the Hipparcos data when it comes to star clusters.
Long-duration gamma ray bursts (1993–2003) Long-duration bursts are associated with the deaths of massive stars in a specific kind of supernova-like event commonly referred to as a collapsar. However, there are also long-duration GRBs that show evidence against an associated supernova, such as the Swift event GRB 060614.
Cosmic age problem (1920s-1990s) The estimated age of the universe was around 3 to 8 billion years younger than estimates of the ages of the oldest stars in the Milky Way. Better estimates for the distances to the stars, and the recognition of the accelerating expansion of the universe, reconciled the age estimates.
Nature of quasars (1950s-1980s) The nature of quasars was not understood for decades. They are now accepted as a type of active galaxy where the enormous energy output results from matter falling into a massive black hole in the centre of the galaxy.