After years of setbacks, the perspective of neuroprotective stroke therapy has revived in light of recent study results. We outline in this review how a neuroprotective candidate drug should be developed, beginning with a thorough preclinical evaluation according to the STAIR (Stroke Therapy Academic Industry Roundtable) criteria. Assessing the safety of the candidate drug in the relatively straightforward Phase IIA would be the first step into clinical development. While advancing into Phase IIB, the implementation of a responder analysis, the use of a surrogate biomarker as well as the use of Bayesian methodology should be considered to increase the likelihood of seeing any therapeutic sign. Clinical development in Phase III should consider that previously used dichotomized endpoints appropriate for evaluation of thrombolytic drugs are likely to be insufficient for assessing efficacy of neuroprotective drugs. Detection of a clinically relevant shift in the outcome measure appears to be a more relevant approach for the type of drug that achieves a reduction and not a reverse of the ischaemic lesion.