We have described in D. discoideum a highly organized cell aggregation that is mediated by cAMP. After suitable differentiation induced by starvation, the cells develop the capacity to orient in gradients of cAMP and to secrete cAMP in response to cAMP. This signaling response sets up the cell-cell relay of cAMP waves that transiently orients the cells toward the center. Both the signaling response and the chemotactic response, measured in isolated cells, adapt. The kinetics and properties of adaptation of the two responses are similar and may be due to the same mechanism. The mechanism does not involve protein synthesis, a change in the number or affinity of surface receptors, or the activation of adenylate cyclase. Adaptation of signaling is essential for the oscillatory production of cAMP at the aggregation centers and ensures that the cAMP waves move steadily toward the edge of the aggregation territories. Adaptation of the chemotactic response also ensures that cells do not reorient away from the center in the gradient presented by the trailing edge of the wave. We have demonstrated that both chemotaxis and cAMP signaling are mediated by the same surface receptor. The polypeptide containing the binding site of the receptor has been identified by photoaffinity labeling with [32P]-8-N3-cAMP as a diffuse band of 41,000-45,000 Mr. The receptor and adenylate cyclase copurify on a homogeneous class of vesicles resistant to extraction by nonionic detergents. A GTP-binding protein that is a substrate for cholera toxin-catalyzed ADP ribosylation is found in supernatants and membranes and may be similar to the Gs regulatory protein of adenylate cyclase in higher organisms. The mechanism of activation of the adenylate cyclase and chemotactic machinery is unknown. We have been able to inhibit the activation of the adenylate cyclase selectively and rapidly with agents acting to crosslink cell surface components, which may give a clue to the activation mechanism. The elaborate mechanisms of cell-cell communication occurring in D. discoideum are without precedent in biological literature, although models of oscillatory wave propagation have been proposed to account for pattern formation. Although it is unlikely that extracellular cAMP would be involved, it is not inconceivable that such mechanisms occur during the development of more evolutionarily advanced organisms. The organized communication system in D. discoideum is only apparent when cells are plated uniformly on a flat surface; such organized movements occurring in a three-dimensional structure such as an embryo would be very difficult to discern.