Adenosine, an intercellular messenger that is a product of the metabolism of ATP, plays a major role in neuronal and vascular responses of the retina to alterations in oxygen delivery. Significant changes in adenosine concentration have been measured in the retina during both ischemia and during the subsequent reperfusion period which result in important, but complex, functional effects. Adenosine A1 receptor stimulation produces a protective effect during ischemia, whereas overstimulation of the A2a receptor has deleterious effects. The mechanisms underlying these findings have not been completely determined, but most likely are the result of alterations in excitotoxicity, gene expression, and blood flow. Paradoxically, prolonged increases in adenosine concentration may be injurious to the retina, a consequence of superoxide radical formation secondary to adenosine catabolism. Adenosine is a critical mediator of blood flow changes in response to ischemia. It is a significant component of the retina's compensatory hyperemic response to ischemia, hypoxia, and hypoglycemia. Increasing endogenous adenosine concentrations may be useful in ameliorating post-ischemic hypoperfusion. Overall, current evidence suggests that adenosine is a vital component of the endogenous retinal response to substrate deprivation. Additionally, in vitro studies provide strong evidence that adenosine is a mediator of the formation and effects of vascular endothelial growth factor, which in turn promotes neovascularization. Finally, the ability of the retina to develop an ischemia-tolerant state by ischemic preconditioning is an intriguing phenomenon that reveals yet another essential role for adenosine in the retina's endogenous response to ischemia. The experimental results described in this review suggest that continued investigation into the role of adenosine in the retina may lead to important clinical applications for adenosine-based therapies that could decrease the incidence of retinal damage in ischemic vasculopathies such as diabetes, glaucoma, and retinal vascular occlusion.