Noninvasive in vivo molecular imaging has developed over the past decade and involves nuclear (Positron emission tomography (PET), gamma camera), magnetic resonance, and in vivo optical imaging systems. Most current in vivo molecular imaging strategies are "indirect" and involve the coupling of a "reporter gene" with a complimentary "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; they can be constitutive leading to continuous transcription and used to identify the site of transduction and to monitor the level and duration of gene (vector) activity. Alternatively, they can be inducible leading to controlled gene expression, or they can function as a sensor element to monitor the level of endogenous promoters and transcription factors. Several examples of imaging endogenous biological processes in animals using reporter constructs, radiolabelled probes and PET imaging are reviewed (p53-dependent gene expression and T-cell receptor-dependent activation of T-lymphocytes). Issues related to the translation of non-invasive molecular imaging technology into the clinic are discussed.