Trafficking of metabolites across the outer mitochondrial membrane is believed to be mediated primarily by the pore forming oltage-ependent anion channel, VDAC (also known as mitochondrial porin). An expanding body of in vitro studies strongly suggest that the pore formed by VDAC can be regulated in a number of ways that implicate it as a site for the regulation of mitochondrial function, yet technical limitations have prevented the extension these studies to a relevant cellular context. The goal of this review is to evaluate recent data that examines the role of mammalian VDAC isoforms using genetic approaches that allow a careful and focused examination of the function of this protein, both in individual cells and in specific tissues. These studies implicate VDAC as a participant in the regulation of intracellular Ca2+ homeostasis and in apoptotic programs; two processes that may be interconnected.