The actions of adenosine on a number of adenylate cyclase systems have been investigated. Nearly all adenylate cyclases examined have been found to contain two receptors for adenosine actions; one, termed P, mediates inhibition and appears to be located on the inner surface of the plasma membrane, and the other, termed R, mediates activation and is located at the external cell surface. An exception to the above generalizations is the fat cell, which contains an adenylate cyclase that is inhibited by adenosine action at both the P and R sites. Adenosine action at the fat cell R site leads to inhibition of the activation of adenylate cyclase elicited by hormones, such as catecholamines and ACTH. The activation by these hormones and the inhibition by adenosine are mediated by distinct GTP-dependent processes. These findings not only explain the potent effects of adenosine on fat cell metabolism, but illustrate the phenomenon of antagonism between two ligands (hormone and adenosine) which act at separate cell surface receptors to modify adenylate cyclase activity.