The significance of receptor heterogeneity has, in many cases, been unclear, particularly in the case of closely related receptor subtypes that are activated by the same endogenous ligands and appear to signal through the same second messenger pathways. In this article, recent studies of the EP and FP prostanoid receptors are reviewed, showing that receptor subtypes previously thought to activate the same signaling pathways, in fact, differ through novel interactions with phosphatidylinositol 3-kinase and activation of nuclear signaling pathways. These findings might be applicable to other families of G-protein-coupled receptors and have implications in cancer and other diseases.