The transcription factor nuclear factor kappa-B (NF-kappaB) is involved in regulating responses of neurons to activation of several different signaling pathways in a variety of physiological and pathological settings. During development of the nervous system NF-kappaB is activated in growing neurons by neurotrophic factors and can induce the expression of genes involved in cell differentiation and survival. In the mature nervous system NF-kappaB is activated in synapses in response to excitatory synaptic transmission and may play a pivotal role in processes such as learning and memory. NF-kappaB is activated in neurons and glial cells in acute neurodegenerative conditions such as stroke and traumatic injury, as well as in chronic neurodegenerative conditions such as Alzheimer's disease. Activation of NF-kappaB in neurons can promote their survival by inducing the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and the antioxidant enzyme Mn-superoxide dismutase. On the other hand, by inducing the production and release of inflammatory cytokines, reactive oxygen molecules and excitotoxins, activation of NF-kappaB in microglia and astrocytes may contribute to neuronal degeneration. Emerging findings suggest roles for NF-kappaB as a mediator of effects of behavioral and dietary factors on neuronal plasticity. NF-kappaB provides an attractive target for the development of novel therapeutic approaches for a range of neurological disorders.