The authors review emerging data evaluating impedance- and optical-based label-free instruments for GPCR drug discovery. In comparison with traditional GPCR assays, they highlight strengths, weaknesses and future opportunities for label-free biosensors. The ability to qualitatively distinguish G-protein coupling has groundbreaking potential for assessing functional selectivity, a concept that is changing the way GPCR pharmacology is defined and screening strategies are designed.