The adenosine receptors (ARs) in the nervous system act as a kind of “go-between” to regulate the release of neurotransmitters (this includes all known neurotransmitters) and the action of neuromodulators (e.g., neuropeptides, neurotrophic factors). Receptor–receptor interactions and AR–transporter interplay occur as part of the adenosine’s attempt to control synaptic transmission. A_2AARs are more abundant in the striatum and A₁ARs in the hippocampus, but both receptors interfere with the efficiency and plasticity-regulated synaptic transmission in most brain areas. The omnipresence of adenosine and A_2A and A₁ ARs in all nervous system cells (neurons and glia), together with the intensive release of adenosine following insults, makes adenosine a kind of “maestro” of the tripartite synapse in the homeostatic coordination of the brain function. Under physiological conditions, both A_2A and A₁ ARs play an important role in sleep and arousal, cognition, memory and learning, whereas under pathological conditions (e.g., Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, epilepsy, drug addiction, pain, schizophrenia, depression), ARs operate a time/circumstance window where in some circumstances A₁AR agonists may predominate as early neuroprotectors, and in other circumstances A_2AAR antagonists may alter the outcomes of some of the pathological deficiencies. In some circumstances, and depending on the therapeutic window, the use of A_2AAR agonists may be initially beneficial; however, at later time points, the use of A_2AAR antagonists proved beneficial in several pathologies. Since selective ligands for A₁ and A_2A ARs are now entering clinical trials, the time has come to determine the role of these receptors in neurological and psychiatric diseases and identify therapies that will alter the outcomes of these diseases, therefore providing a hopeful future for the patients who suffer from these diseases.