G-protein-coupled receptors (GPCRs) are a widespread family of transmembrane receptors with different
physiologically relevant functions. Alterations in the structure and function of these receptors at different levels (ligand
binding, signaling and trafficking) may result in a number of pathological conditions which represent a major health problem.
Mutations in these receptors are also linked to different inherited diseases for which there is no cure to date. Rationale
design, based on receptor structural knowledge, is needed for the discovery of novel drugs with higher selectivity and
less side effects. In fact, about 50% of the drugs currently under development target this kind of receptors. Oligomerization
among GPCRs has been clearly established from experimental, particularly in vitro, studies. Moreover, homo and heterodimerization
provide new unexpected clues for explaining the molecular mechanisms underlying some diseases in
which GPCRs signaling might be affected. In this review we will analyze GPCRs structure and function for a better understanding
of the dimerization process and the experimental approaches currently used to detect such interactions. Furthermore,
how drugs targeting heteromers can represent new opportunities to tackle novel and safer treatments of some
pathologies will be described. Recent results, in this regard, will be reported as encouraging examples in the field. Finally,
the newest technologies available for developing drugs targeting heteromers will also be reviewed highlighting the importance
of bivalent ligands that emerge as very powerful molecules interacting with heteromers.