Adenosine is involved as an endogenous modulator of nerve and glial cell functions in pathological processes occurring in conditions of hypoxia/hypoglycemia and also in neurodegenerative diseases. Thus, adenosine levels rise rapidly in the brain areas affected by ischemic insult; it reduces excitatory amino acid release and Ca 2+ influx. This results in neuroprotective actions. There is evidence that both A 1 and A 2A adenosine receptors, in an opposite manner, are involved in this process. Stimulation of A 1 receptors in isolated neurons or brain slices and in animal models of stroke produces neuroprotection. The same net effect is achieved in models of either global or focal ischemia with blockade of A 2A adenosine receptors by a variety of nonselective and selective adenosine receptor antagonists. This apparent paradox can be explained by considering that stimulation of either A 1 or A 2A receptors exerts opposing effects on excitotoxic neuronal glutamate release and a differential regulation of the potentially neurotoxic microglial cell functions. These adenosine effects seem to be determined by the cellular activation state and achieved by influencing the size and timing of intracellular Ca 2+ and cAMP signals, balancing the pathologically altered cross-talk of these second messengers. Whether a reinforcement of the adenosine-controlled second messenger generation, an enhancement of A 1 receptor stimulation or a blockade of A 2A receptors, or a combined approach better supports neuroprotection presumably depends on the nature of the pathological process and on the timepoint at which the pharmacological intervention is started.