G-protein-coupled receptors (GPCRs) are membrane proteins that convert extracellular information into intracellular signals. They are involved in many biological processes and therefore represent powerful targets to modulate physiological and pathological states. Recent studies have demonstrated that GPCR activity is regulated by several mechanisms. Among these, protein-protein interactions (and in particular interactions with other receptors leading to heteromerization) has been shown to have an important role in modulating GPCR function. This has expanded their repertoire of signaling and added a new level of regulation to their physiological roles. Emerging studies provide evidence for tissue-specific and disease-specific receptor heteromerization. This suggests that heteromers represent novel drug targets for the identification of selective compounds with potentially fewer side-effects.