One of the best-described transmembrane signal transduction mechanisms is based on receptor activation of the alpha subunit of the heterotrimeric G protein Gs, 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 Gs alpha pathways in Drosophila wing epithelial cells. These genetic studies show that the Gs alpha 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.