Stroke is a leading cause of death and disability worldwide and an increasing number of ischemic stroke patients are undergoing pharmacological and mechanical reperfusion. Both human and experimental models of reperfused ischemic stroke have implicated the complement cascade in secondary tissue injury. Most data point to the lectin and alternative pathways as key to activation, and C3a and C5a binding of their receptors as critical effectors of injury. During periods of thrombolysis use to treat stroke, acute experimental complement cascade blockade has been found to rescue tissue and improves functional outcome. Blockade of the complement cascade during the period of tissue reorganization, repair, and recovery is by contrast not helpful and in fact is likely to be deleterious with emerging data suggesting downstream upregulation of the cascade might even facilitate recovery. Successful clinical translation will require the right clinical setting and pharmacologic strategies that are capable of targeting the key effectors early while not inhibiting delayed repair. Early reports in a variety of disease states suggest that such pharmacologic strategies appear to have a favorable risk profile and offer substantial hope for patients.