Members of the nuclear factor kappaB (NF-kappaB) family of transcription factors are activated within the CNS in pathological settings of apoptosis and neurological disease. Recent work using several model systems provides accumulating evidence that these transcription factors also participate in the regulation of neuronal activity-dependent transcription and behavior under physiological conditions. This review highlights advances in our understanding of the mechanisms of Ca(2+)-responsive activation and synaptic signaling to the nucleus by NF-kappaB transcription factors within the CNS, and the relevance of this transcription factor family for learning and memory.