BAX and BAK are the essential effector proteins that promote mitochondrial outer membrane permeabilisation (MOMP) and cell death during apoptosis. Understanding the protein interactions that control their deadly apoptotic activity will identify new ways to target apoptosis therapeutically. VDAC2 is thought to be a critical inhibitor of the pro-apoptotic protein BAK. Our studies challenge this dogma. Our data indicate that VDAC2 is important for efficient mitochondrial localisation of both BAX and BAK and is an essential promoter of BAX apoptotic function. Cells lacking VDAC2 and BAK are largely resistant to apoptosis induced by diverse stimuli including BH3-mimetics and deletion of VDAC2 alone was sufficient to protect cells from BAX-dependent apoptosis both in vitro and in vivo. Moreover, deletion of VDAC2 accelerates MYC-driven AML confirming that VDAC2 is also a key mediator of BAX apoptotic function in the context of oncogenic stress as well as chemotherapy. Thus, disrupting the interaction of BAX (and perhaps also BAK) with VDAC2 is a potential mechanism of chemoresistance or to impair unwanted or damaging apoptosis for example following ischemic stroke or reperfusion injury.