The following brief summary is based on a recent wx review by Rubin and Baserga 1, and the reader is referred to that review for extended references. A simplified representation of the IGF system includes 3 receptors, 3 ligands and 6 IGF binding proteins Ž. Ž IGFBPs. The ligands are the mature IGF-I 70. Ž. aminoacids, the mature IGF-II 67 aminoacids and insulin. The receptors are the type I insulin-like Ž. growth factor receptor IGF-IR, the insulin receptor Ž. Ž. IR and the IGF-II receptor IGF-IIR. In terms of cellular proliferation, the IGF-IR is the most active of Ž. the 3 receptors see below: it is activated by all 3 ligands, and, although it has several functional feawx tures in common with the IR 2, the ß subunit of the IGF-IR is 10 times more mitogenic than the beta wx subunit of the IR 3. Insulin at supraphysiological concentrations also activates the IGF-IR; this is an important point to remember, because when insulin is used at μg concentrations, it exerts its mitogenic wx stimulation through the IGF-IR 4. Under appropriate conditions, the IR is mitogenic. The IGF-IIR, per se, does not stimulate cell proliferation: in fact, deletion of the IGF-IIR genes causes Ž. an increase in body weight of mice see below. It is now considered as a down-regulator of IGF-II, ie a way for the organism and the cells to regulate the availability of IGF-II. The availability of IGF-I and IGF-II is also regulated by the six IGFBPs, that can Ž serve as a storage site for these ligands insulin does