Recent evidence has suggested that neuropeptides, and in particular substance P (SP), may play a critical role in the development of morphological injury and functional deficits following acute insults to the brain. Few studies, however, have examined the role of SP, and more generally, neurogenic inflammation, in the pathophysiology of traumatic brain injury and stroke. Those studies that have been reported suggest that SP is released following injury to the CNS and facilitates the increased permeability of the blood brain barrier, the development of vasogenic edema and the subsequent cell death and functional deficits that are associated with these events. Inhibition of the SP activity, either through inhibition of the neuropeptide release or the use of SP receptor antagonists, have consistently resulted in profound decreases in edema formation and marked improvements in functional outcome. The current review summarizes the role of SP in acute brain injury, focussing on its properties as a neurotransmitter and the potential for SP to adversely affect outcome.