G protein-coupled receptors (GPCRs) control all the main physiological functions and are targeted by more than 50% of therapeutics. Our perception of GPCRs signalling has grown increasingly complex since it is now accepted that they activate large signalling networks which are integrating the information fluxes into appropriate biological responses. These concepts lead the way to the development of pathway-selective agonists (or antagonists) with fewer side effects. Systems biology approaches focused on GPCR-mediated signalling would help dealing with the huge complexity of these mechanisms therefore speeding-up the discovery of new drug classes. In this review, we present the various technical and conceptual possibilities allowing a systems approach of GPCR-mediated signalling. The main remaining limitations are also discussed.