Major molecular abnormalities in breast cancer include the deregulation of several components of the IGF system. It is well recognized that the epithelial breast cancer cells commonly overexpress the IGF-I receptor while IGF-II is expressed by the tumor stroma. In view to the fact that the IGF-IR has mitogenic, pro-invasive and anti-apoptotic effects and mediates resistance to a variety of anti-cancer therapies, breast cancer is expected to be a candidate to therapeutic approaches aimed to inhibit the IGF-IR. However, there is increasing awareness that IGF system in cancer undergoes signal diversification by various mechanisms. One of these mechanisms is the aberrant expression of insulin receptor (IR) isoform A (IR-A), which is a high affinity receptor for both insulin and IGF-II, in breast cancer cells. Moreover, overexpression of both IGF-IR and IR-A in breast cancer cells, leads to overexpression of hybrid IR/IGF-IR receptors (HRs) as well. Upon binding to IGF-II, both IR-A and HRs may activate unique signaling patterns, which predominantly mediate proliferative effects. A better understanding of IGF system signal diversification in breast cancer has important implications for cancer prevention measures, which should include control of insulin resistance and associated hyperinsulinemia. Moreover, in addition to the IGF-IR, both IR-A and HRs should be also considered as molecular targets for anti-cancer therapies.