In this review, we have described the role of adenosine A2A receptor-driven interactions with other neurotransmitter systems, at multiple levels of psychopharmacology, from the molecular basis of receptor-receptor cross-talk, to pharmacological and genetic manipulations of A2AR activity, and the alteration of neuropsychiatric phenotypes in psychostimulant addiction, anxiety and depression, schizophrenia and learning and memory. This evidence concerns the gene ADORA2A and drug dependence.