The nine membrane-bound isoforms of the enzyme adenylate cyclase (EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting through G protein-coupled receptors to modulate intracellular cAMP levels. In general, acute activation of Galpha(s)-coupled receptors stimulates cAMP accumulation, whereas acute activation of Galpha(i/o)-coupled receptors typically inhibits cAMP accumulation. It is also well established that persistent activation of G-protein coupled receptors will alter subsequent drug-modulated cAMP accumulation. These alterations are thought to represent cellular adaptive responses following prolonged receptor activation. One phenomenon commonly observed, heterologous sensitization of adenylate cyclase, is characterized by an enhanced responsiveness to drug-stimulated cAMP accumulation following persistent activation of Galpha(i/o)-coupled receptors. Heterologous sensitization of adenylate cyclase was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory receptors. Such an adaptive mechanism has been suggested to play a role in the processes of addiction to and withdrawal from many drugs of abuse and in psychiatric disorders including schizophrenia and depression. Although the precise mechanisms remain unknown, research over the last decade has led to advances toward understanding the molecular events associated with heterologous sensitization of recombinant and endogenous adenylate cyclases in cellular models. These events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified Galpha(s)-dependent events that are involved in the expression of heterologous sensitization.