Although a number of secondary injury factors are known to contribute to the development of morphological injury and functional deficits following traumatic brain injury, accumulating evidence has suggested that neuropeptides, and in particular substance P, may play a critical role. Substance P is released early following acute injury to the CNS as part of a neurogenic inflammatory response. In so doing, it facilitates an increase in the permeability of the blood-brain barrier and the development of vasogenic edema. At the cellular level, substance P has been shown to directly result in neuronal cell death; functionally, substance P has been implicated in learning and memory, mood and anxiety, stress mechanisms, emotion-processing, migraine, emesis, pain, and seizures, all of which may be adversely affected after brain injury. Inhibition of post-traumatic substance P activity, either by preventing release or by antagonism of the neurokinin-1 receptor, has consistently resulted in a profound decrease in development of edema and marked improvements in functional outcome. This review summarizes the current evidence supporting a role for substance P in acute brain injury.