Antithrombotic strategies have provided the most benefit to patients with ischemic stroke. Of these, the acute use of recombinant tissue plasminogen activator (rt-PA) has been shown to significantly increase the number of patients who suffer little or no residual disability. Experimental work indicated that early reperfusion of occluded brainsupplying arteries reduces the size of injury and improves outcome in several species. However, there has been little progress to increase the proportion of patients who are benefitted by acute intervention with PAs since the initial report. Clinical trial experience highlights limitations in a number of aspects of design and outcome which suggest refinements for future trials. Experimental work suggests that improved outcome is also possible with acute intervention using other antithrombotic agents. There is considerable opportunity to explore safe strategies which could further benefit stroke outcome. Copyright (C) 2004 S. Karger AG, Basel.