Background and Purpose: A large number of GPCRs are potentially valuable drug targets but remain understudied. Many of these lack well-validated activating ligands and are considered “orphan” receptors, and G protein coupling profiles have not been defined for many orphan GPCRs. Here we asked if constitutive receptor activity can be used to determine G protein coupling profiles of orphan GPCRs. Experimental Approach: We monitored GDP-sensitive interactions (coupling) between 48 understudied orphan GPCRs and five G proteins (240 combinations) using bioluminescence resonance energy transfer (BRET). No activating ligands were used. Constitutive BRET between the same receptors and β-arrestins was also measured. Key Results: We found sufficient GDP-sensitive BRET to generate G protein coupling profiles for 22 of the 48 receptors we studied. Altogether we identified 48 coupled receptor-G protein pairs, many of which have not been described previously. Conclusion and Implications: We conclude that receptor-G protein complexes that form spontaneously in the absence of guanine nucleotides can be used to profile G protein coupling of constitutively active GPCRs. This approach may prove useful for studying G protein coupling of other GPCRs for which activating ligands are not available.