Neuroprotective drugs are known to reduce neurological damage in animal models of stroke, but none are generally accepted for the treatment of patients with acute stroke. Thrombolytic therapy with alteplase (recombinant tissue-type plasminogen activator; rt-PA) has been shown to improve outcomes in patients with stroke, but it must be given quite rapidly after stroke onset. The efficacy of alteplase therapy has proven that acute treatment is possible, and methods used in those trials will be applicable to neuroprotective development. A variety of neuroprotective drugs have already been tested and more trials are likely. Glutamate antagonists have been most extensively evaluated, but they are relatively disappointing since they have phencyclidine-like adverse events that limit the tolerable doses. Several other classes of neuroprotectives are in development, although their mechanisms of action are not well established. Combinations of neuroprotectives and thrombolytics are likely to be tested in clinical trials in the near future.