The electromagnetic spectrum contains different frequency bands useful for medical imaging and therapy. Short wavelengths (ionizing radiation) are commonly used for radiological and radionuclide imaging and for cancer radiation therapy. Intermediate wavelengths (optical radiation) are useful for more localized imaging and for photodynamic therapy (PDT). Finally, longer wavelengths are the basis for magnetic resonance imaging and for hyperthermia treatments. Recently, there has been a surge of interest for new biomedical methods that synergize optical and ionizing radiation by exploiting the ability of ionizing radiation to stimulate optical emissions. These physical phenomena, together known as radioluminescence, are being used for applications as diverse as radionuclide imaging, radiation therapy monitoring, phototherapy, and nanoparticle-based molecular imaging. This review provides a comprehensive treatment of the physics of radioluminescence and includes simple analytical models to estimate the luminescence yield of scintillators and nanoscintillators, Cherenkov radiation, air fluorescence, and biologically endogenous radioluminescence. Examples of methods that use radioluminescence for diagnostic or therapeutic applications are reviewed and analyzed in light of these quantitative physical models of radioluminescence.