Nimesulide is a preferential inhibitor of cyclooxygenase-2 (COX-2) and it is one of the most prescribed non-steroidal anti-inflammatory drugs (NSAID) worldwide. Nimesulide was recently shown to have neuroprotective properties in animal models of acute neurologic injury. In particular, nimesulide is highly effective in reducing ischemic brain injury. This neuroprotective efficacy has been demonstrated in animal models of transient and permanent focal cerebral ischemia, global brain ischemia, embolic stroke, and chronic cerebral hypoperfusion. Nimesulide has been shown to reduce infarction, improve neurological function, attenuate blood-brain barrier disruption and edema, and reduce leukocyte infiltration into the ischemic brain. These beneficial effects have been observed even when the first treatment is given several hours after the onset of ischemia, demonstrating the wide therapeutic time window for nimesulide's neuroprotection. This is of great relevance since most stroke patients reach the emergency room several hours after the onset of symptoms, a time at which most medical interventions are not effective. In addition, nimesulide produces a long-lasting neuroprotection. This is of importance since some 'neuroprotective' compounds only produce a delay in cell death, and not a permanent protection. Its several mechanisms of action in neuroprotection make nimesulide a desirable and promising candidate as therapy for acute brain ischemia. This article reviews recent knowledge on the effects of nimesulide against brain injury, with particular emphasis in cerebral ischemia, and makes a critical appraisal of its therapeutic potential in the management of patients with brain ischemia.