G protein-coupled receptors (GPCRs) form one of the largest protein families found in nature. This chapter discusses mutagenesis strategies aimed at identifying receptor-G protein contact sites, as well as residues on the G protein a subunits (Ga) that are critical for determining the selectivity of receptor/G protein interactions. It deals with “split” GPCRs and their potential usefulness for studying molecular aspects of GPCR assembly. To understand the structural details involved in receptor–G protein recognition and G protein activation, specific, functionally relevant receptor–G protein contact sites need to be identified. Several different experimental approaches have been used to elucidate the G protein coupling profiles of individual GPCRs. Receptor and G protein mutations were generated using different polymerase chain reaction-based mutagenesis strategies. Such information is crucial for the proper interpretation of mutagenesis data since mutant GPCRs are frequently retained in an intracellular compartment.