Today's medical imaging technologies are expected to furnish anatomic, physiologic, molecular, and genomic information for accurate disease diagnosis, prediction of treatment response, and development of highly specific and sensitive drugs and imaging agents. However, none of the current imaging methods used in humans provides comprehensive medical imaging. To harness the strengths of different imaging methods, multimodality imaging has become an attractive strategy for in vivo studies. Beyond small-animal imaging, a less frequently used multimodality imaging strategy is the fusion of radionuclear and optical methods. This less frequent use is probably attributable to some misconceptions, technical difficulties, or a lack of appreciation for the benefits of the 2 methods in patient care. This minireview addresses some of these concerns, with emphasis on the potential applications of multimodality optical and SPECT/PET systems.