Cerebral ischemia leads to brain damage caused by pathogenetic mechanisms that are also activated by neurotrauma. These mechanisms include among others excitotoxicity, over production of free radicals, inflammation and apoptosis. Furthermore, cerebral ischemia and trauma both trigger similar auto-protective mechanisms including the production of heat shock proteins, anti-inflammatory cytokines and endogenous antioxidants. Neuroprotective therapy aims at minimizing the activation of toxic pathways and at enhancing the activity of endogenous neuroprotective mechanisms. The similarities in the damage-producing and endogenous auto-protective mechanisms may imply that neuroprotective compounds found to be active against one of these conditions may indeed be also protective in the other. This review summarizes the pathogenetic events of ischemic and traumatic brain injury and reviews the neuroprotective strategies employed thus far in each of these conditions with a special emphasize on their clinical relevance and on future directions in the field of neuronal protection.