The G protein α-subunit G_sα is required for hormone-stimulated cAMP generation. In pancreatic β cells, G_sα mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of β cell survival and insulin release. Studies have suggested that G_sα/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with β cell-specific G_sα deficiency (βGsKO) were generated by mating G_sα-floxed mice to rat insulin II promoter-cre recombinase mice. βGsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. βGsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. βGsKO mice had markedly reduced average islet size and β cell mass, which was partially explained by reduced β cell size. In addition, βGsKO mice had significantly reduced β cell proliferation and increased β cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on β cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that G_sα/cAMP pathways are critical regulators of β cell function and proliferation that can work through IRS2-independent mechanisms.