Reasons for the unsatisfactory number and reliability of most trials on the pharmacological treatment of acute cerebral ischemia are reviewed, focusing mainly on the clinical aspects of the issue. The opportunity of early intervention, supported by current pathophysiological hypotheses, is recognized. Past and recent Italian trials on ischemic stroke patients evaluated and treated within the first 6 h from onset are reported, also mentioning the results of a study including early cerebral angiography and SPECT (Single Photon Emission Computed Tomography). Early fibrinolytics associated to brain protecting agents are regarded as the future choice in clinical trials of acute cerebral ischemia.