The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca2 + overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood–brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca2 + overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion.