Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the established treatment for acute ischemic stroke patients presenting within 4.5 h of stroke onset based on the results of the National Institute of Neurological Disorders and Stroke Study Group trial and European Cooperative Acute Stroke Study III. In a significant number of patients, however, intravenous thrombolysis with rt-PA remains ineffective, with lower rates of recanalization, especially for proximal occlusions and a large thrombus burden. Newer thrombolytic agents, such as reteplase, tenecteplase or desmoteplase, offer pharmacokinetic and hemodynamic advantages over rt-PA and have been, or are currently being, tested for safety and efficacy in clinical trials. Agents such as direct fibrinolytics that do not depend on the availability of plasminogen are also being studied in ongoing trials. Endovascular revascularization is an evolving treatment option enabling mechanical clot disruption or extraction in combination with local directed pharmacological thrombolysis. Several new endovascular devices have been successfully tested for safety in acute ischemic stroke patients and are now being tested for efficacy in larger clinical trials. Continued innovation and refinement of endovascular technology and techniques, including combination therapy such as bridging therapy and the use of stent-like devices, is expected to increase technical success and improve overall efficacy and time to recanalization with minimal procedure-related morbidity in the treatment of acute ischemic stroke.