Since their discovery, G protein-coupled receptors (GPCRs) constitute one of the most studied proteins leading to important discoveries and perspectives in terms of their biology and implication in physiology and pathophysiology. This is mostly linked to the remarkable advances in the development and application of the biophysical resonance energy transfer (RET)-based approaches, including bioluminescence and fluorescence resonance energy transfer (BRET and FRET, respectively). Indeed, BRET and FRET have been extensively applied to study different aspects of GPCR functioning such as their activation and regulation either statically or dynamically, in real-time and intact cells. Consequently, our view on GPCRs has considerably changed opening new challenges for the study of GPCRs in their native tissues in the aim to get more knowledge on how these receptors control the biological responses. Moreover, the technological aspect of this field of research promises further developments for robust and reliable new RET-based assays that may be compatible with high-throughput screening as well as drug discovery programs.