This perspective on the report by McCampbell et al. in this issue of the journal (beginning on page 290) addresses the role of insulin receptor substrate (IRS) proteins in cancer progression. The IRS proteins link many cell-surface receptors to signal transduction pathways. Activation of the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin axis normally results in serine phosphorylation and subsequent downregulation of these adaptor proteins. The authors show that changes in the negative feedback regulation of IRS proteins is associated with the progression of endometrial epithelial cells to hyperplasia and cancer. Therefore, understanding the function of adaptor proteins could provide additional strategies for cancer prevention and treatment.