The activity of membrane-bound platelet adenylate cyclase, when stimulated in vitro by several compounds (including fluoride), is significantly reduced in alcoholics compared with control subjects. We have begun a study of the genetics of this enzyme activity. Complex segregation analysis of basal (unstimulated) platelet adenylate cyclase activity in families reveals a mode of inheritance that cannot be accounted for by a simple mixed model of transmission. By contrast, adenylate cyclase activity stimulated by fluoride ion reveals a single major locus effect with a modest multifactorial background. These results suggest that a single factor in the second-messenger pathway may (a) account for the majority of individual differences in stimulation of adenylate cyclase of fluoride and (b) help explain the reduced activities previously observed in alcoholics.