Extracellular adenine nucleotides interact with P2-purinergic receptors to regulate a broad range of physiological processes. These receptors include the P2Y-, P2U-, P2T-, P2X-, and P2Z-purinergic receptor subtypes. This review focuses on the first three of these receptor subtypes, which couple to G proteins and regulate the inositol lipid, cyclic AMP, and other second-messenger signaling cascades. Both pharmacological data and the occurrence of selectivity of coupling to second-messenger pathways indicate the existence of multiple members in several of the classes of P2-purinergic receptor subtypes. Complementary DNAs cloned for P2Y- and P2U-purinergic receptors predict proteins with seven transmembrane-spanning motifs, typical of that of other G protein-linked receptors.