G protein-coupled receptors (GPCRs) have been proven to be the largest family of druggable targets in the human genome. Given the importance of GPCRs as drug targets and the de-orphanization of novel targets, GPCRs are likely to remain the frequent targets of many drug discovery programs. Traditionally, molecular assays dominate in the process of GPCR drug discovery and development. With recent advances in instrumentation and pathway deconvolution of GPCR ligand-induced biosensor signatures, label-free biosensor-enabled cell-based assays have become a very active area for GPCR screening. This article reviews the principles, current status and future directions of leading label-free technology platforms for GPCR drug discovery.