The existence of A(2A)-D-2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A(2A) and D-2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A(2A)-D-2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A(2A) and D-2 agonists. The A(2A)-D-2 heteromers, could either be A(2A)-D-2 heterodimers and/or higher-order A(2A)-D-2 hetero-oligomers. In striatal neurons there are probably A(2A)-D-2 heteromeric complexes, together with A(2A)-D-2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A(2A) and D-2 signaling in the striatopallidal GABA neurons. Through the use of D-2/D-1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A(2A)-D-2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D-2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A(2A) receptor. Computerized modeling of A(2A)-D-2 heteromers are in line with these findings. It seems likely that A(2A) receptor-induced reduction of D-2 receptor recognition, G protein coupling, and signaling, as well as the existence of A(2A)-D-2 co-trafficking, are the consequence of the existence of an A(2A)-D-2 receptor heteromer. The relevance of A(2A)-D-2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A(2A)-D-3 heteromeric receptor complexes in cotransfected cell lines has been summarized.