The Rel/NF-kappaB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-kappaB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-kappaB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-kappaB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-kappaB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-kappaB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-kappaB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-kappaB signaling pathway as a promising target for cancer prevention and treatment.