The nuclear transcription factors kappaB (NF-kappaB) function as key regulators of physiological processes in the central nervous system. Aberrant regulation of NF-kappaB can underlie neurological disorders associated with neurodegeneration. A large number of studies have reported a dual role of NF-kappaB in regulating neuron survival in pathological conditions. A recent progress in understanding the mechanisms responsible for opposite effects elicited by NF-kappaB in brain dysfunctions arises from the identification of diverse NF-kappaB complexes specifically involved in the mechanism of neuronal cell death or cell survival. We here discuss the latest findings and consider the therapeutic potential of targeting distinct NF-kappaB complexes for the treatment of neurodegenerative disorders and memory dysfunctions.