The adenosine A(2A) receptor (A(2A)R) is in the center of a neuromodulatory network affecting a wide range of neuropsychiatric functions by interacting with and integrating several neurotransmitter systems, especially dopaminergic and glutamatergic neurotransmission. These interactions and integrations occur at multiple levels, including (1) direct receptor- receptor cross-talk at the cell membrane, (2) intracellular second messenger systems, (3) trans-synaptic actions via striatal collaterals or interneurons in the striatum, (4) and interactions at the network level of the basal ganglia. Consequently, A(2A)Rs constitute a novel target to modulate various psychiatric conditions. In the present review we will first summarize the molecular interaction of adenosine receptors with other neurotransmitter systems and then discuss the potential applications of A(2A)R agonists and antagonists in physiological and pathophysiological conditions, such as psychostimulant action, drug addiction, anxiety, depression, schizophrenia and learning and memory.