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Molecular-genetic imaging in living organisms has become a new field with the exceptional growth over the past 5 years. Modern imaging is based on three technologies: nuclear, magnetic resonance and optical imaging. Most current molecular-genetic imaging strategies are “indirect,” coupling a “reporter gene” with a complimentary “reporter probe.” The reporter transgene usually encodes for an enzyme, receptor or transporter that selectively interacts with a radiolabeled probe and results in accumulation of radioactivity in the transduced cell. In addition, reporter systems based on the expression of fluorescence or bioluminescence proteins are becoming more widely applied in small animal imaging. This review begins with a description of Positron Emission Tomography (PET)-based imaging genes and their complimentary radiolabeled probes that we think will be the first to enter clinical trials. Then we describe other imaging genes, mostly for optical imaging, which have been developed by investigators working with a variety of disease models in mice. Such optical reporters are unlikely to enter the clinic, at least not in the near-term. Reporter gene constructs can be driven by constitutive promoter elements and used to monitor gene therapy vectors and the efficacy of gene targeting and transduction, as well as to monitor adoptive cell-based therapies. Inducible promoters can be used as “sensors” to monitor endogenous cell processes, including specific intracellular molecular-genetic events and the activity of signaling pathways, by regulating the magnitude of reporter gene expression.