Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A(1) receptors (A(1)Rs) and the less abundant, but widespread, facilitatory A(2A)Rs. It is commonly assumed that A(1)Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A(1)R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A(1)Rs in chronic noxious situations. In contrast, A(2A)Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A(2A)R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A(2A)R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A(2A)R blockade compared to A(1)R activation does not mean that A(1)R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A(2A)R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A(1)Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.