Alpha-melanocyte stimulating hormone (alpha-MSH) and other melanocortins make up a family of endogenous peptides derived from pro-opiomelanocortin. Through binding to five melanocortin receptors (MCR), these peptides exert multiple influences on the host, including anti-inflammatory and immunomodulatory effects. The wide distribution of at least three melanocortin receptor subtypes (MC1R, MC3R and MC4R) in neural, glial and endothelial cells suggests that these receptors could be pharmacological targets for neuroprotective therapies. As a consequence of modulation of NF-kappaB-mediated transcription, melanocortins reduce production of pro-inflammatory agents in brain cells after injury. During brain ischemia, alpha-MSH and other melanocortins exert protective influences with a broad time window. Further, melanocortins rescue neurons subjected to excitotoxic insults, accelerate neurophysiological recovery after spinal cord injury and increase regenerative capacity of peripheral nerves in postlesion repair. Based on their established actions, melanocortins could form a novel class of therapeutic agents for acute and chronic disorders of the nervous system.