Stroke is the third most common cause of death in the USA, following heart disease and cancer. Intravenous recombinant tissue plasminogen activator is the only US FDA-approved pharmacological treatment available today for acute ischemic stroke. Despite the approval of this drug, it has been underutilized in the community. The limited time window of 3 h disqualifies many patients from receiving the drug. In addition, fears of intracranial hemorrhage have resulted in underutilization of the drug in the community setting. Efforts to increase the time window of treatment include utilization of the intra-arterial route for delivery of a thrombolytic drug and interventional mechanical strategies. In this article, we review the major intravenous and intra-arterial thrombolysis trials and review the mechanical strategies being developed to treat patients with acute ischemic stroke.