Regulators of G-protein signaling (RGS) are a family of highly diverse, multifunctional signaling proteins that enhance the intrinsic GTPase rate of certain heterotrimeric G-protein alpha subunits. New findings indicate that RGS proteins act not only as dedicated G-protein inhibitors, but rather as tightly regulated modulators of many aspects of G-protein signaling. Like other RGS proteins, RGS2 lacks GTPase-activating protein activity for Gsalpha; however, it directly inhibits the activity of several adenylyl cyclase (AC) isoforms. This article discusses methods, including AC binding assays, cAMP accumulation assays, in vitro AC activity assays, and gel filtration, used to identify the interaction site of RGS2 and type V adenylyl cyclase.