Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein G z (Gα z ). Clues to one potential function recently emerged with the finding that activation of Gα z inhibits glucose‐stimulated insulin secretion (GSIS) in an insulinoma cell line [Kimple et al. (2005) J Biol Chem 280:31708]. To extend this study in vivo , a Gα z knock‐out mouse model was utilized. No differences were discovered in the islet physiology or morphology or the insulin sensitivity of Gα z ‐null mice and wild‐type controls. Gα z ‐null mice did, however, display increased plasma insulin concentrations and glucose clearance following glucose challenge as compared to wild‐type controls. The increased plasma insulin observed in Gα z ‐null mice is likely a direct result of enhanced insulin secretion, as pancreatic islets isolated from Gα z ‐null mice exhibited significantly higher GSIS than those of wild‐type mice. Finally, the increased insulin secretion observed in Gα z ‐null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Gα z ‐null islets in the absence of exogenous stimulation. These findings indicate that Gα z may be a potential new target for therapeutics aimed at ameliorating β‐cell dysfunction in Type 2 diabetes. This work was supported by NIH grants DK67799 to M.E.K, DK42583 to C.B.N., and GM55717 to P.J.C.