Therapeutic options in the acute phase of a stroke are limited despite a great number of neuroprotectant drugs that have been developed in the last few decades. Although neuroprotection has been proved in animal models, translation of experimental efficacy into clinical benefit in humans is a difficult task. With the aim of bringing closer laboratory and clinical results, a change and unification of the methodology used is needed. Evaluating neuroprotectant capacity to salvage the penumbra using MRI both in animals and humans as a surrogate outcome can help to select drugs more likely to demonstrate clinical benefit. In addition, neuroprotection should enlarge the window of opportunity for reperfusion therapies and protect vascular structures to reduce reperfusion injury and the clinical complications related to thrombolytic treatment. A better understanding of ischemic and restorative brain mechanisms beyond the acute phase of stroke may open new therapeutic options to improve stroke recovery.