Apoptosis is a physiological process critical for organ development, tissue homeostasis, and elimination of defective or potentially dangerous cells in complex organisms. Apoptosis can be initiated by a wide variety of stimuli, which activate a cell suicide program that is constitutively present in most vertebrate cells. In diverse cell types, Rel/NF-κB transcription factors have been shown to have a role in regulating the apoptotic program, either as essential for the induction of apoptosis or, perhaps more commonly, as blockers of apoptosis. Whether Rel/NF-κB promotes or inhibits apoptosis appears to depend on the specific cell type and the type of inducer. An understanding of the role of Rel/NF-κB transcription factors in controlling apoptosis may lead to the development of therapeutics for a wide variety of human diseases, including neurodegenerative and immune diseases, and cancer.