The goal of acute stroke therapy is preservation of the ischemic penumbra, the geographic area of relatively less ischemia surrounding the profoundly ischemic center. Emergent intravenous revascularization is currently the only U.S. Food and Drug Administration–approved therapy, but intra-arterial revascularization has also been shown to improve outcome significantly. Intravenous therapy has significant limitations: the time window for therapy is short, the large dose of fibrinolytic agent required may increase the risk of hemorrhagic complications, and questions have been raised regarding efficacy in patients with large vessel occlusions. Intra-arterial delivery of the lytic agent can address these issues, and direct intracranial intra-arterial fibrinolysis has been shown to be effective. Thrombolytic agents differ in stability, half-life, and fibrin selectivity, but effective therapies for acute stroke therapy must provide one common denominator: restoration of flow. It now appears certain that direct intra-arterial delivery of fibrinolytic agent improves the efficacy of lysis of bulk thrombus. The Interventional Stroke Therapy Outcomes Registry is acquiring data on all forms of interventional stroke therapy from around the nation as well as outside the United States to identify best practices in the treatment of acute stroke.