Acute ischemic stroke is a major public health threat. Intravenous thrombolysis has been shown in several randomized clinical trials to improve outcomes in selected patients, and intravenous t-PA is currently approved by the FDA for patients presenting within 3 hours of symptom onset. Three generations of thrombolytic agents have been introduced. Intra-arterial thrombolysis offers several potential advantages over intravenous thrombolysis for acute stroke, such as precise diagnosis and the opportunity to reduce the overall dose of thrombolytic agent used, and thus lowers the chance of ICH. The PROACT trials showed that intra-arterial thrombolysis can improve recanalization rates and outcomes in patients presenting with MCA occlusions up to 6 hours after symptom onset. Alternative strategies for endovascular treatment of acute stroke include combination intravenous-intra-arterial administration of thrombolytic agents, use of GP IIb-IIIa antagonists, and mechanical thrombolysis. Options for mechanical thrombolysis include microsnares, the In-Time thrombus retrieval device, angioplasty, and suction thrombectomy. Several investigational devices are undergoing clinical evaluation. The PROACT enrollment criteria can serve as guidelines for patient selection. Radiographic evaluation of acute stroke patients begins with imaging to exclude the presence of ICH; recent developments in CT and MRI perfusion promise to permit identification of patients who will benefit from thrombolysis with greater precision.