Higher eukaryotes, including mammals and plants, express a family of VDAC proteins each encoded by a distinct gene. Two human genes encoding VDAC isoforms (HVDAC1 and HVDAC2) have been characterized in greatest detail. These genes generate three proteins that differ primarily by the addition of distinct N terminal extensions in HVDAC2 and HVDAC2', a splice variant of HVDAC2, relative to HVDAC1. Since N terminal sequences have been demonstrated to target many proteins to appropriate subcellular compartments, this observation raises the possibility that the N terminal differences found in HVDAC isoforms may lead to targeting of each protein to different cellular locations. Consistent with this hypothesis, a large number of reports have provided evidence consistent with the notion that HVDAC1 and its homolog in related mammalian species may specifically be present in the plasma membrane or other nonmitochondrial cellular compartments. Here, we review this information and conclude that if VDAC molecules are present at nonmitochondrial locations in mammalian cells, these are unlikely to be the known products of the HVDAC1 or HVDAC2 genes.