Thrombolytic therapy has revolutionized acute ischemic stroke (AIS) treatment; however it is clear that intravenous (IV) thrombolytic therapy has certain limitations, including a short-time window for use, poor specificity for the site of arterial occlusion, and suboptimal recanalization rates. Some of these problems may be circumvented by using intra-arterial (IA) thrombolysis. In this article, we will discuss the various thrombolytic agents being used in AIS, their mechanisms of actions and doses, and the rationale for use of IA therapy as opposed to IV thrombolysis, and review the clinical trials using IA thrombolysis. We will also discuss other approaches to IA thrombolysis, including mechanical and other endovascular techniques.