Significance Insulin and IGF-1 receptors share many downstream signaling pathways but have unique biological effects. Here, using global phosphoproteomics, we demonstrate that there are important differences in phosphorylation-mediated signaling between IR and IGF1R in both the basal and ligand-stimulated states involving multiple pathways of cellular regulation. Thus, mTORC1 and PIP3/AKT signaling, which are important in metabolism, are preferentially regulated by IR, while Rho GTPases, mitosis, and cell cycle proteins, which are involved in control of cellular growth, are preferentially regulated by IGF1R. These differences can be mapped to effects of both the extracellular and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation, contributing to the unique effects of these hormones.