Abstract: Persistent activation of most Gα_i/o-coupled receptors resulted in enhanced activity of adenylyl cyclase (AC) and subsequent cyclic adenosine monophosphate (cAMP) accumulation within cells, and this phenomenon has generally been referred to as supersensitization of AC. It represents a cellular adaptive response that has been widely believed to be the cause of drug dependence. Supersensitization of AC might have an important impact during the processes of many central nervous system (CNS) disorder diseases, such as schizophrenia and depression, due to altered cell functions. This article provides an overview of the history and present status in our understanding of Gα_i/o-coupled receptor-mediated supersensitization of AC, as well as discussion of the problems and future perspective.