For decades, it has been generally proposed that a given receptor always interacts with a particular GTP-binding protein (G-protein) or with multiple G-proteins within one family. However, for several G-protein-coupled receptors (GPCR), it now becomes generally accepted that simultaneous functional coupling with distinct unrelated G-proteins can be observed, leading to the activation of multiple intracellular effectors with distinct efficacies and/or potencies. Multiplicity in G-protein coupling is frequently observed in artificial expression systems where high densities of receptors are obtained, raising the question of whether such complex signalling reveals artefactual promiscuous coupling or is a genuine property of GPCRs. Multiple biochemical and pharmacological evidence in favour of an intrinsic property of GPCRs were obtained in recent studies. Thus, there are now many examples showing that the coupling to multiple signalling pathways is dependent on the agonist used (agonist trafficking of receptor signals). In addition, the different couplings were demonstrated to involve distinct molecular determinants of the receptor and to show distinct desensitisation kinetics. Such multiplicity of signalling at the level of G-protein coupling leads to a further complexity in the functional response to agonist stimulation of one of the most elaborate cellular transmission systems. Indeed, the physiological relevance of such versatility in signalling associated with a single receptor requires the existence of critical mechanisms of dynamic regulation of the expression, the compartmentalisation, and the activity of the signalling partners. This review aims at summarising the different studies that support the concept of multiplicity of G-protein coupling. The physiological and pharmacological relevance of this coupling promiscuity will be discussed.