Allosteric regulation of ligand binding is a well-established mechanism regulating the function of G protein-coupled receptors (GPCR). Allosteric modulators have been considered so far as molecules binding to an allosteric site, distinct from that of the reference ligand (orthosteric site), and able to modulate the binding affinity at the orthosteric site and/or the signaling properties resulting from orthosteric site occupancy. Given that most GPCR are known to form dimers or higher order oligomers, we explored whether allosteric interactions could also occur between protomers within oligomeric arrays, thereby influencing binding and signaling receptor properties. Two main conclusions emerged from such studies. First, allosteric modulators can affect one receptor by binding to another receptor within a dimeric or oligomeric complex. Second, allosteric modulators might act on a given receptor by targeting the "orthosteric site" in another receptor of the complex. Allosteric regulation within di(oligo)mers thus implies that the pharmacological properties of a given receptor subtype can be influenced by the array of dimerization partners coexpressed in each particular cell type. Ligands could thus act as agonists or antagonists on 1 receptor, while modulating allosterically the function of a variety of other receptors to which they do not bind directly. Allosteric regulation across GPCR oligomeric interfaces is expected to greatly influence the practice of pharmacology. It will likely affect the design of drug discovery programs, which rely mostly on the overexpression of the receptor of interest in a cell line, thereby focusing on homo-oligomers and ignoring the potential effects of other partners.