G protein-coupled receptors (GPCRs) transduce signals from a wide variety of extracellular stimuli such as ions, photons, odors, tastants, hormones, and neurotransmitters and hence are central players in commu- nication between the cells of multicellular organisms and their environment. Characterization of these receptors at the molecular level has shown that GPCRs form dimers or oligomers (for simplicity, herein called dimers), yet their function is just beginning to emerge. The activation of GPCRs as dimers presents the opportunity for trans-activation of receptors, where a ligand-bound GPCR can change the activity of a neighboring GPCR. Trans-activation of GPCRs can take place either via transmembrane domains (TMDs) of two or more receptors or through a ligand-bound extracellular domain (ECD) of one receptor to the TMD of another (referred to as intermolecular cooperation), for GPCRs with a distinct ligand-binding ECD such as the glycoprotein hormone receptors. Before explaining the phenomenon of intermolecular cooperation between domains of GPCR dimers, this chapter first discusses the molecular interactions between GPCR dimers, which leads to trans-activation, and then explains various experimental strategies employed to study the significance of intermolecular cooperation either in rescuing the signaling of mutant GPCRs by complementary receptors or in changing the allosteric properties of GPCR dimers. The physi- ological significance of intermolecular cooperation is also discussed in detail, as well as its clinical significance that lies in the use of agents that selectively activate or inhibit particular signaling pathways or affect GPCR dimer interactions.