The development of noninvasive imaging technologies designed specifically for use with small animals has provided new paradigms for cancer research. Traditional molecular biology techniques are being melded with noninvasive imaging technologies to develop a new research domain, "molecular imaging." One of the most exciting advances in this research area is the adaptation and application of conventional reporter-gene imaging techniques, used extensively by cell and molecular biologists, to living animals. Using these new assays, investigators can image noninvasively, repeatedly, and quantitatively the location, magnitude, and duration of reporter-gene expression in living animals. This review will describe the instrumentation used for noninvasive imaging of reporter genes, the reporter genes developed for noninvasive imaging with radio-nuclide-based assays such as positron emission tomography, and the reporter genes used for optically based noninvasive assays using sensitive charged-coupled device cameras. Applications of noninvasive, whole-animal imaging to gene therapy for cancer, to cell-based therapy for cancer, to lymphocyte activation, to cancer progression and dissemination in engrafted models, to tumor initiation, promotion and metastasis in conditional murine models of cancer induction, and to the noninvasive monitoring of tumor responses to a variety of therapies are described. New developments in multimodality molecular imaging are discussed, and the potential utility of noninvasive reporter gene expression in the diagnosis and management of human cancer is presented.