Mitochondria play a critical role in apoptosis induction in response to myriad stimuli. These organelles release proteins into the cytosol which trigger caspase activation or perform other functions relevant to apoptosis, including cytochrome c (cyt-c), caspases, AIF, and SMAC (Diablo). The mechanisms by which these proteins escape from mitochondria remain enigmatic. Moreover, it is unclear whether release of these proteins versus disturbances in core mitochondrial functions represents the cell death commitment mechanism. In this regard, suppression of apoptosis using broad-spectrum caspase inhibitory compounds has been reported in many circumstances to prevent the morphological and biochemical manifestations of apoptosis, and yet not protect cells from death and not preserve clonigenic survival. Thus, while mitochondrial damage can be coupled to caspase activation pathways, cell death commitment often occurs upstream of caspase activation when mitochondria-dependent cell death pathways are invoked. Here, we review evidence implicating dysregulation of cellular pH as a component of the cell death mechanism involving mitochondria. Cell Death and Differentiation (2000) 7, 1155 - 1165