Reperfusion injury is believed to represent an important facet of brain disease initiated by ischemia. With the continued improvement toward clinically relevant animal models of stroke and cerebrovascular injury, more direct evidence for reperfusion injury after brain ischemia will be obtained. Experimental studies should consider which outcome measures are most clinically relevant and utilize chronic histopathological and behavioral assessments to monitor outcome. Recent data indicate a complex and time-dependent sequence of microvascular and cellular responses to brain injury. The potential for pathophysiological events occurring at different reperfusion periods indicates that multiple therapeutic windows may exist for brain protection. Thus, it is conceivable that successful therapeutic strategies may ultimately involve several agents directed at the early, intermediate, and late phases of reperfusion. Finally, it should be stressed that reperfusion injury may represent a chronic condition that could potentially participate in a wide range of central nervous system disorders including those associated with normal aging.