In early trials of thrombolysis, unenhanced CT was used to exclude patients with brain hemorrhage or large infarctions but was insensitive to stroke pathophysiology or early signs of cerebral ischemia or infarction. Currently, CT angiography, CT perfusion, and MR imaging can provide information about stroke mechanisms and prognosis, quantify penumbral tissue, and support risk stratification and patient selection. This article reviews the role of neuroimaging in the original intravenous thrombolytic trials, current application of these technologies, and the potential future role of imaging to extend the time window for thrombolysis and to augment therapeutic success.