In the last decade, a huge number of drugs have been developed in order to block the different molecular reactions of the ischemic cascade. Most of neuroprotective compounds decrease infarct volume in experimental stroke models, but none of them has reduced stroke mortality and morbidity in clinical trials. This article comments those factors that justify discrepancies between the laboratory and clinical findings, and reviews the neuroprotective drugs studied in patients with acute ischemic stroke. Although the clinical investigation of many of them has been abandoned because safety concerns, preliminary observations suggest a beneficial effect of ebselen, a compound with antioxidant activity, and citicoline, a stabiliser of cell membranes. Other neuroprotective drugs like trafermin and glycine antagonists are in advanced clinical investigation, thus the neuroprotection scenario may favourably change in the near future.