G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for around a third of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. Current receptor assay systems are based on measurement of either ligand displacement or downstream functional responses, rather than direct observation of ligand binding. Issues of allosteric modulation, probe dependence, and functional selectivity create challenges in selecting suitable assay formats. Therefore, a method that directly measures GPCR-ligand interactions, independent of binding site, probe, and signaling pathway would be a useful primary and orthogonal screening method. An alternative ligand discovery strategy would be the direct measurement of GPCR-ligand interactions by label-free technologies, such as surface plasmon resonance (SPR). In this chapter, we summarize overview of the SPR technology and development of applications for detection of ligand binding to GPCRs using wild-type and thermostabilized receptors. We discuss the utilization of SPR as a biophysical screening method for fragment-based drug discovery for GPCRs. In particular, we show how SPR screening can detect both orthosteric and allosteric ligands with the appropriate experimental design.