Trafficking of metabolites across the outer mitochondrial membrane is believed to be mediated primarily by the pore-forming voltage-dependent anion channel, VDAC (also known as mitochondrial porin). An expanding body of in vitro studies have 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 brief review is to summarize recent data that examine the role of VDAC and its regulation in the context not of the isolated protein or organelles but in cells, focusing on the application of genetic strategies in a number of experimental systems.