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G protein-coupled receptors (GPCRs) play a central role in cellular communication, converting external stimuli into intracellular responses. GPCRs bind a very broad panel of ligands, such as hormones, neurotransmitters, peptides and lipids. Ligand binding triggers a series of receptor conformational rearrangements, enabling the coupling to intracellular partners and the activation of signaling cascades. The major breakthrough in GPCRs structural biology of the past decade has considerably advanced our understanding of GPCR activation. However, structural information cannot fully explain the molecular details of GPCRs pharmacology. Biophysical investigations reveal that GPCRs are very dynamic proteins, capable of exploring a wide range of conformational states. Binding to ligands of various pharmacological classes, as well as intracellular effectors and allosteric modulators, can shift the equilibrium between these states and the kinetic of interconversions among the different conformers. Investigation of GPCR dynamic interplay is therefore important to better understand the complex pharmacology and signaling profile of these receptors.