The Bcl-2 family of proteins consists of anti-apoptotic and pro-apoptotic members, which determine the life or death of cells by altering mitochondrial membrane permeability. Pro-apoptotic Bcl-2 family members increase mitochondrial membrane permeability, resulting in the release of mitochondrial apoptogenic factors such as cytochrome c that activates death proteases called caspases, whereas anti-apoptotic family members prevent this increase of mitochondrial membrane permeability. The release of cytochrome c is central to apoptotic signal transduction in mammals, and has been studied extensively, leading to the development of several models for cytochrome c release including rupture of the mitochondrial outer membrane and involvement of specific channels. This article describes the important role of a mitochondrial outer membrane channel, the voltage-dependent anion channel (VDAC), in apoptogenic cytochrome c release and its regulation by Bcl-2 family members, and also discusses the molecular architecture of the life–death switch in mammalian cells. Cell Death and Differentiation (2000) 7, 1174–1181