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Accurate diagnosis and treatment of various pathologic conditions can be achieved by integrating multimodal imaging systems that furnish complementary information to improve patient management. The availability of high-resolution tomography systems, fast computers, and image reconstruction algorithms has improved disease diagnosis and treatment management. As medical practice moves into the molecular era, the realization that no single imaging method can provide solutions to the complex information derived from molecular imaging has heightened interest in the use of multimodal imaging to harness the strengths of different imaging methods. For example, co-registration of pathologic tissues with computed tomography (CT) and radionuclear platform provides complementary anatomical and functional diagnostic information, respectively. Optical imaging (OI) promises to complement established imaging methods by reporting molecular events with high detection sensitivity. Although combining molecular optical contrasts with MRI or CT provides co-registered reference anatomy, the disparate contrast agent concentrations needed for OI and MRI or CT present a barrier to integration. An alternative approach is to combine OI with an established imaging modality possessing similar detection sensitivity but complementary reporting strategies. Because of the high sensitivity of both nuclear and OI methods and the compatibility of their imaging agents, incorporating nuclear to OI will provide a unique opportunity to fuse the imaging datasets with identical pharmacokinetics but different contrast mechanisms. To appreciate the potential benefits of combining optical and SPECT/PET, we have tabulated the similarities and differences between the two imaging methods in Table 1 (1). Based on these properties, several potential opportunities to combine the two platforms become apparent.