Currently, the most important therapeutic approaches in the acute phase of ischemic stroke are focused on the restoration of regional cerebral blood flow, early admission to a stroke unit and the attempt to block, using neuroprotective drugs, the biochemical and metabolic changes involved in the ‘ischemic cascade’. Treatment with rt-PA in the acute phase, although very effective, is still limited to a small number of patients and positive preclinical results of neuroprotective treatment have not, as yet, been endorsed in clinical trials. The remarkable lack of concordance between the positive results in experimental models and the negative results obtained in clinical trials has led to a change in attitude in the conduct of preclinical studies as well as to a modification of the design of clinical trials, with special attention being paid to patient selection criteria and clinical evaluation. Some neuroprotective drugs, such as citicoline, have shown some efficacy in subgroups of patients with cerebral infarction, even with a therapeutic window of up to 24 h, which would suggest a possible neurorestorative effect. Different degrees of functional recovery, weeks or months after the ischemic event, are currently observed in clinical practice and have been related to endogenous self-repair mechanisms. The growing understanding of the mechanisms involved in the phenomena of brain plasticity and their modulation, together with the possibility of restoring functional deficits by encouraging endogenous neurogenesis or by cell therapy, open up new directions in the treatment of stroke patients.