Abstract Experience with fibrinolytic agents in acute cerebral ischemia models supports several conclusions: (i) the presence or stimulation of endogenous t-PA, u-PA, and the appropriate plasminogen activator inhibitors has not been well-studied in acute cerebral ischemia animal model systems; (ii) recent studies have focused on the rather obvious assertion that fibrinolytic agents may produce thrombus lysis in acute cerebrovascular thrombotic occlusions; (iii) early intervention with rt-PA may result in more rapid thrombus lysis, earlier recovery of function, and decreased mortality in small animal stroke thromboembolism models; (iv) rt-PA has no effect on clinical recovery following MCA occlusion and reperfusion in the non-human primate at dose-rates capable of producing very high circulating t-PA levels; and (v) in several model systems, intravenous infusion of rt-PA early after ischemia/infarction by several methods is, not associated with significant intracerebral hemorrhage. Despite the plethora of well-described animal models of acute cerebral ischemia described, few have been employed in extensive studies of the effect of fibrinolytic agents in acute ischemia. Of those reported, no single model addresses more than a single hypothesis with respect to the intervention with a fibrinolytic in acute cerebral ischemia. Of the models available, the non-human primate provides the most relevant setting for the investigation of acute cerebrovascular ischemia and the hemorrhagic consequences in the central nervous system of the use of thrombolytic agents. On the other hand, questions of mortality may be addressed by population studies in small animal models. Other small animal model studies, particularly in the rabbit, have confirmed the observations in other organ systems that thrombus lysis produces reperfusion in the vascular bed under scrutiny.