Up to the mid-1990 s, the treatment of acute ischemic stroke was almost anecdotal. The introduction of systemic thrombolysis dramatically changed the scenario improving patient outcomes and becoming the standard of care for patients who present within 3 h from the onset of symptoms. Other options, such as intraarterial thrombolysis, or different mechanical reperfusion approaches, have been tested in the past few years. The benefit-risk profile of these approaches is discussed in this review. The current main challenge in the therapy of acute stroke is to define the optimal strategy for patients excluded from thrombolysis because of delayed presentation or older age and for patients treated with thrombolysis that do not reperfuse.