G protein-coupled receptors (GPCRs) transduce signals from cell surface to intracellular effectors through various G proteins. In this chapter, a luciferase reporter gene assay system is described for the study of the coupling of GPCRs to G alpha 12/13. This assay system, in which ligand-stimulated production of the reporter luciferase under the control of a modified serum-responsive element (SRE) in a cell line derived from mice lacking G alpha q/11 that are transfected with a GPCR of interest, allows for easy, fast, and valid determination of the coupling of the GPCR to G alpha 12/13.