Obesity is increasingly recognized as an important health problem in developed, industrialized countries. As a large proportion of the variance in individual adiposity is based on genetic factors (1-3), recent efforts have focused on identifying genes involved in regulating the percentage of body fat in a given individual. This effort is helped by the existence of rodent models of genetic obesity. Many strains of mice and at least three rat strains have been identified thus far that exhibit inherited obesity accompanied by a similar set of endocrine abnormalities (4). Although the symptoms of the disease are similar in different strains, different genes appear to be involved in causing the syndrome, as the mutation responsible for the obesity maps to different chromosomal sites in the different strains. Efforts to find the products of the mutated genes over the past 30 years have generally been unsuccessful. However, the available data imply that many obesity mutations may involve genes that code for proteins in a single signal transduction pathway or one particular cascade of covalent modification. Reasonable theories are plentiful about the identity of such a pathway, but current studies in the laboratories of the authors suggest that the A1 adenosine receptor signaling pathway may be involved. Evidence of abnormal A1 receptor function has been obtained from studies of Zucker rats and obese (ob/ob) mice (5-7). These strains are obese because of a single recessive mutation. Measurements of adenylyl cyclase activity and regulation in isolated adipocytes and isolated plasma membranes suggest that the receptor is unusually and tonically active in obese rats. Because signaling from this receptor inhibits lipolysis in white and brown fat, induces insulin resistance in skeletal muscle (8, 9), but increases insulin sensitivity in adipose tissue (10, 11), the possibility arises that the excessive activity of the A1 adenosine receptor may induce obesity. Data from human volunteers are also compatible with the possibility that the activity of the receptor is unusually high in vivo in obese individuals (12).