Stroke is the second or third major cause of death in the “industrialized countries.” About 30% of patients die within a year after the first insult, and 20% remain dependent on care. So far there is no effective therapy available but one is desperately needed. At present worldwide many pharmacotherapeutic approaches are under preclinical and clinical investigation in which the focus is on agents that counteract the deleterious effects of excessively released excitatory neurotransmitters such as glutamate. Recently the endogenous nucleoside adenosine or its reinforcement has been demonstrated to exert a variety of actions that counteract ischemia-induced brain damage. In this chapter we briefly review and discuss the experimental evidence for this hypothesis in the framework of the pathophysiology of brain ischemia. The corresponding literature has been extensively reviewed in a recent publication [1]. We therefore only include newer references.