AbstractInsulin‐like growth factors (IGFs) provide essential signals for the control of embryonic and postnatal development in vertebrate species. In mammals, IGFs act through and are regulated by a system of receptors, binding proteins, and related proteases. In each of the many tissues dependent on this family of growth factors, this system generates a complex interaction specific to the tissue concerned. Studies carried out over the last decade, mostly with transgenic and gene knockout mouse models, have demonstrated considerable variety in the cell type–specific and developmental stage–specific functions of IGF signals. Brain, muscle, bone, cartilage, pancreas, ovary, skin, and fat tissue have been identified as major in vivo targets for IGFs. Concentrating on several of these organ systems, we review here phenotypic analyses of mice with genetically modified IGF systems. Much progress has also been made in understanding the specific intracellular signaling cascades initiated by the binding of circulating IGFs to their cognate receptor. We also summarize the most relevant aspects of this research. Considerable efforts are currently focused on deciphering the functional specificities of intracellular pathways, particularly the molecular mechanisms by which cells distinguish growth‐stimulating insulin‐like signals from metabolic insulin signals. Finally, there is a growing body of evidence implicating IGF signaling in lifespan control, and it has recently been shown that this function has been conserved throughout evolution. Very rapid progress in this domain seems to indicate that longevity may be subject to IGF‐dependent neuroendocrine regulation and that certain periods of the life cycle may be particularly important in the determination of individual lifespan. Birth Defects Research (Part C) 69:257–271, 2003. © 2003 Wiley‐Liss, Inc.