All prior drug development programs of neuroprotective agents were unsuccessful for a variety of reasons related to both preclinical assessment and the design/implementation of clinical trials. The neuroprotection hypothesis of improving functional outcome related to salvaging ischemic brain tissue is strongly supported by robust preclinical data for many agents. In the future, monotherapy neuroprotection trials will be difficult but could be performed in underused centers with drugs that have very promising and complete preclinical results. Additional approaches for the testing and use of neuroprotective agents should be considered. Novel approaches would include extending penumbral survival for the later use of reperfusion therapy, reducing reperfusion injury after successful reperfusion, and using drugs with both neuroprotective and recovery enhancing effects, as exemplified by granulocyte colony-stimulating factor and citicoline. To maximize outcome after stroke, the combined use or reperfusion and neuroprotection is likely to be needed, so we must begin to perform carefully designed trials with this combination.