Resveratrol (RS) exerts a large number of cell-protective and anti-tumor effects, among them the induction of tumor cell apoptosis. Since the bioavailability of ingested RS at distant organs is low and apoptosis induction often requires relatively high RS levels (above 20 μmol/l), this polyphenolic food ingredient might be particularly effective as a chemopreventive in the digestive tract. Previous studies have suggested that chemoprevention by non-steroidal anti-inflammatory drugs (NSAIDs) is blunted by the loss of a single component of the apoptotic machinery - the Bax protein. Here, we report that RS efficiently provokes apoptosis in human colorectal carcinoma cells deficient for Bax, although at a reduced rate compared to the parental cells, through the activation of the mitochondrial death pathway. Knockdown of pro-apoptotic Bak by RNA interference reduced the apoptotic response to a similar extent as Bax deficiency in the parental cells and completely abolished apoptosis in Bax-null cells. Notably, although negative for RS-induced, mitochondria-mediated apoptosis, Bax+Bak double-deficient cells were sensitized by RS to ligand-induced, death receptor-mediated apoptosis. Thus, in contrast to NSAIDs, RS may remain effective as a pro-apoptotic chemopreventive as long as Bax and Bak have not both been inactivated during clonal selection.