Over the past several years, nuclear imaging modalities such as PET and SPECT have received much attention because they have been instrumental not only in preclinical cancer research but also in nuclear medicine. Yet nuclear imaging is limited by high instrumentation cost and subsequently low availability to basic researchers. Cerenkov radiation, a relativistic physical phenomenon that was discovered 70 years ago, has recently become an intriguing subject of study in molecular imaging because of its potential in augmenting nuclear imaging, particularly in preclinical small-animal studies. The intrinsic capability of radionuclides emitting luminescent light from decay is promising because of the possibility of bridging nuclear imaging with optical imaging-a modality that is much less expensive, is easier to use, and has higher throughput than its nuclear counterpart. Thus, with the maturation of this novel imaging technology using Cerenkov radiation, which is termed Cerenkov luminescence imaging, it is foreseeable that advances in both nuclear imaging and preclinical research involving radioisotopes will be significantly accelerated in the near future.