Editor’s summary Bioluminescence resonance energy transfer (BRET)–based biosensors are commonly used to determine the specific G proteins that are activated by a particular G protein–coupled receptor (GPCR). Wright et al. found that the type of biosensor and other aspects of the experimental design, such as whether the receptor was tagged and the specific Gβ and Gγ subunits expressed in the cells, influenced whether the assay detected GPCR coupling to a particular Gα subunit.