PET-based molecular-genetic imaging is part of a larger base of three imaging technologies (nuclear, magnetic resonance, and optical) incorporating methods that are established in molecular and cell biology. Most current molecular imaging strategies are "indirect", coupling a "reporter gene" with a complimentary "reporter probe". Reporter gene constructs driven by constitutive promoter elements can be used to monitor transduced cells in adoptive therapies as well as gene therapy vectors. Inducible promoters function as sensor elements and can be used to provide information about endogenous gene regulation, mRNA stabilization, and specific protein-protein interactions; the promoter can also be cell specific, allowing expression of the transgene to be restricted to certain cells and organs. Several examples of PET imaging of endogenous cell processes are reviewed, the advantages of multimodality imaging are emphasized, and the prospects for translation into the clinic are discussed.