Any therapeutic trial of a new treatment for stroke must provide sufficient reliable evidence to convince clinicians and healthcare purchasers of its merits. Clinicians are most likely to be convinced by large independent studies that provide clear evidence of benefit. If the trial is really to alter healthcare delivery, it should also confirm that the treatment is cost-effective enough to satisfy the increasingly critical demands of the healthcare purchasers. Although some of the current trials will be able to detect large benefits, reliable detection of the moderate benefits that seem more plausible with neuroprotection will need to wait until completion of trials that are perhaps an order of magnitude larger. If tens of thousands of patients are to be recruited into trials of neuroprotective therapy, it is essential that the trials have simple practicable designs that allow participation not only by interested university hospitals but also busy general hospitals with few research resources.