Guanine nucleotide binding proteins (G proteins) play key roles in signal transduction, including the coupling of hormone and neurotransmitter receptors to adenylate cyclase, ion channels, and polyphosphoinositide metabolism. One member of this family of proteins, G_s, appears to represent a specific site of action of ethanol in the central nervous system. Ethanol is often perceived as a nonspecific drug, and its anesthetic effects may in fact arise from relatively nonspecific interactions with cell membrane lipids. However, recent investigations point to a selective effect of low concentrations of ethanol to promote the activation of G_s, and thus to enhance adenylate cyclase activity. Ethanol seems to have little or no effect on the function of other identified G proteins. After chronic ingestion of ethanol by animals, or chronic exposure of cells in culture to ethanol, the sensitivity of adenylate cyclase to stimulation by guanine nucleotides and agonists that act via G_s is decreased. The mechanism of this change may involve qualitative and/or quantitative alterations in G_s, and seems to vary in different cell types. Studies of human platelets and lymphocytes also reveal differences in adenylate cyclase activity between alcoholics and control subjects.∗∗∗ The differences are consistent with involvement of G_s, and do not appear to reverse upon cessation of alcohol exposure. The results suggest that the platelet and/or lymphocyte adenylate cyclase system may provide a biochemical marker of genetic predisposition to alcoholism.—Hoffman, P. L.; Tabakoff, B. Ethanol and guanine nucleotide binding proteins: a selective interaction. FASEB J. 4: 2612‐2622, 1990.