G protein-coupled receptors (GPCRs) were assumed to exist and function in the plasma membrane as monomeric proteins that became activated by binding of one agonist ligand to one receptor molecule (Bourne et al., 1990). However, although previous findings based on rather indirect measures such as radioligand binding had suggested a direct interaction of two receptors with each other (Limbird et al., 1975; Ferre et al., 1991), it was the application of a protein-protein interaction assay by bioluminescence resonance energy transfer (BRET) that revealed the phenomenon of molecular proximity between beta2-adrenergic receptors in living cells (Angers et al., 2000). Since then, this topic has been a major subject of research and numerous in silico and in vitro studies have suggested expression of family A GPCRs as homodimers and higher-order homomers in heterologous expression systems. However, the demonstration that reconstitution of a single beta2-adrenergic receptor molecule into lipoprotein particles leads to efficient activation of G proteins raised concerns about the functional significance of family A GPCR homomers (Whorton et al., 2007), and this is currently a controversial topic (for an extensive review on GPCR homodimers/homomers, see Milligan, 2013; see also Bouvier and Hebert, 2014; Lambert and Javitch, 2014). Another fundamental yet relatively independent question is that related to expression of different GPCR subtypes as heteromers. It is well accepted that the family C GABAB receptor needs two protomers (GABAB-R1 and GABAB-R2) to reach the plasma membrane as a functional dimeric receptor (Jones et al., 1998; Kaupmann et al., 1998; White et al., 1998). On the other hand, although multiple lines of evidence indicate that family A GPCR heteromers may exist, particularly in tissue cultures (Gonzalez-Maeso, 2011; Ferre et al., 2014), only relatively recent studies started to test this formulation in whole animal models.