Noninvasive molecular imaging has developed over the past decade and involves nuclear (positron emission tomography [PET], gamma camera), magnetic resonance, and optical imaging systems. Most current molecular imaging strategies are "indirect" and involve the coupling of a "reporter gene" with a complementary "reporter probe." Imaging the level of probe accumulation provides indirect information related to the level of reporter gene expression. Reporter gene constructs are driven by upstream promoter/enhancer elements; reporter gene expression can be leading to continuous transcription and used to identify the site of transduction and to monitor the level and duration of gene (vector) activity. Alternatively, reporter gene expression can be leading to controlled gene expression, or reporter genes can function as a "sensor" to monitor the level of endogenous promoters and transcription factors. The development of versatile and sensitive assays that do require tissue sampling will be of considerable value for monitoring molecular-genetic and cellular processes in animal models of human disease, as well as for studies in human subjects in the future. Noninvasive imaging of molecular-genetic and cellular processes will complement established molecular-biologic assays that require tissue sampling, and will provide a spatial as well as a temporal dimension to our understanding of various diseases. Several examples of imaging endogenous biologic processes in animals using reporter constructs, radiolabeled probes, and PET imaging are reviewed (e.g., p53-dependent gene expression, T-cell receptor-dependent activation of T-lymphocytes, and preliminary studies of endogenous HIF-1alpha expression). Issues related to the translation of noninvasive molecular imaging technology into the clinic are also discussed.