The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra. This could serve as a biomarker indicative of neuroprotective potential and could increase likelihood of success in clinical studies by allowing selection of patients who are most likely to respond to therapy.