Neuroprotective drugs aimed at limiting infarct size, prolonging the therapeutic window for thrombolysis, or minimizing postischemic reperfusion injury and inflammation, have demonstrated excellent results in experimental models of ischemia, but lack of efficacy in clinical trials and were often associated with serious side effects. Criticism has been leveled at each stage in the development progress from preclinical testing to trial analysis. However, by elaborating guidelines for assessing the adequacy of preclinical testing and by optimizing eligibility criteria, dose selection, control of confounding factors, and end points in clinical trials, the prospects of success will increase. Combination of reperfusion strategies with neuroprotection, combination of agents targeting different mechanisms of the ischemic cascade, and nonpharmacologic neuroprotection, such as hypothermia, all seem quite promising...