Nuclear factor-kappaB (NF-kappaB) is generally viewed as anti-apoptotic and oncogenic, leading to a quest for its inhibitors. However, recent evidence suggests that in some situations NF-kappaB may promote apoptosis. Depending on the specific cell type and the stimulus involved, NF-kappaB activation may lead to either anti- or pro-apoptotic response. Both these effects can be mediated by NF-kappaB in a context-dependent manner by selectively regulating its target genes. In this review, we discuss the evidence for NF-kappaB's pro-apoptotic role and explore the possible mechanisms behind it. We emphasize that rather than trying to inhibit NF-kappaB in cancer therapy, agents should be developed to unleash its pro-apoptotic ability.