One of the best-described transmembrane signal transduction mechanisms is based on receptor activation of the α subunit of the heterotrimeric G protein G s , leading to stimulation of adenylyl cyclase and the production of cAMP. Intracellular cAMP is then thought to mediate its effects largely, if not entirely, by activation of protein kinase A and the subsequent phosphorylation of substrates which in turn control diverse cellular phenomena. In this report we demonstrate, by two different methods, that reduction or elimination of protein kinase A activity had no effect on phenotypes generated by activation of G s α pathways in Drosophila wing epithelial cells. These genetic studies show that the G s α pathway mediates its primary effects by a novel pathway in differentiating wing epithelial cells. This novel pathway may in part be responsible for some of the complex, cell-specific responses observed following activation of this pathway in different cell types.