G protein-coupled receptors (GPCRs) are a big family of membrane proteins which represent one of the main classes of drug targets. However, their investigation presents several challenges, among which their instability outside the membrane environment. Different strategies for the drug discovery of this target are available, and surface plasmon resonance (SPR) stands out as one of the most informative and widespread binding assays, with many advantages such as real-time and label-free analyses resulting in the definition of both affinity and kinetic constants. This review covers the applications of SPR in GPCR drug discovery of the last 10 years and classifies the papers based on the immobilization strategy on the SPR sensor chip to maintain receptor stability. In particular, GPCR immobilization can occur in its native membrane by immobilizing whole cells or membrane fragments, using membrane mimetics (such as lipoparticles, lentiviral particles, liposomes, lipoproteins, nanodiscs, or planar lipid membranes) or immobilizing the isolated receptor stabilized by the use of detergents or engineering approaches. Different examples were considered and pros and cons of each strategy were presented.