In this review we provide a conceptual overview of radiopharmaceuticals containing positron-emitting isotopes, not a catalog of radiopharmaceuticals or details of syntheses. We hope to provide an integrated framework for understanding the radiopharmaceuticals that are available at this time, describing both their strengths and weaknesses, and to look forward to some of the improvements that might be anticipated in the next decade. The range of biology that can be studied with positron emission tomography (PET) radiopharmaceuticals has greatly expanded, involving more sophisticated tracers and more sophisticated data analysis. PET measurements now encompass increasingly more specific aspects of human biochemistry and physiology as described in this review. As the biology being studied becomes more complex, the demands on the radiopharmaceutical and the methods of data analysis also become more complex. New synthetic chemistry and data analysis must develop in tandem. Radiopharmaceuticals must be designed to ensure that the rate determining step that is of interest is the one reflected in the data from the radiopharmaceutical. The challenge to the PET community of chemists, biologists, and physicians is to apply new knowledge of human biochemistry for developing and validating useful PET radiopharmaceuticals that will, in turn, produce useful nuclear medicine procedures. Initially the synthesis of a compound containing a short-lived radionuclide was a triumph in itself. However as the science advances the radiochemical synthesis becomes just the first step in a long trail that terminates in the compound being used to provide data on biological processes via a well-designed PET experiment. The resulting list of compounds and experiments should be as diverse as all of human biology and pathophysiology.