Throughout evolution the brain has acquired elegant strategies to protect itself against a variety of environmental insults. Prominent among these are signals released from injured cells that are capable of initiating a cascade of events in neurons and glia designed to prevent further damage. Recent research has identified a remarkably large number of neuroprotection factors (NPFs), whose expression is increased in response to brain injury. Examples include the neurotrophins (NGF, NT-3, NT-5, and BDNF), bFGF, IGFs, TGFs, TNFs and secreted forms of the beta-amyloid precursor protein. Animal and cell culture studies have shown that NPFs can attenuate neuronal injury initiated by insults believed to be relevant to the pathophysiology of traumatic brain injury (TBI) including excitotoxins, ischemia, and free radicals. Studies of the mechanism of action of these NPFs indicate that they enhance cellular systems involved in maintenance of Ca2+ homeostasis and free radical metabolism. Recent work has identified several low-molecular-weight lipophilic compounds that appear to mimic the action of NPFs by activating signal transduction cascades involving tyrosine phosphorylation. Such compounds, alone or in combination with antioxidants and calcium-stabilizing agents, have proved beneficial in animal studies of ischemic brain injury and provide opportunities for development of preventative/therapeutic approaches for TBI.