Data from the European Cooperative Acute Stroke Study (ECASS) III trial demonstrated that tissue plasminogen activator given up to 4.5 h after stroke onset improves outcome and treatment guidelines support its use during this time window. Intra-arterial therapy with tissue plasminogen activator or devices is commonly used at large tertiary centers up to 6–8 h after stroke onset, but conclusive evidence of efficacy remains lacking. During the acute phase after stroke onset, blood pressure elevations should be reduced as should substantial elevations in blood glucose. Statins are recommended in essentially all non-cardioembolic stroke patients. The most important future directions for acute stroke therapy are to extend the therapeutic time window and to increase the proportion of patients treated within the currently documented 4.5-h time window. Imaging-guided selection of appropriate patients will likely be a key factor for extending the therapeutic time window and both diffusion/perfusion MRI and perfusion computed tomography will be useful imaging modalities in this effort.