Podocytes are crucial for preventing the passage of albumin into the urine and when lost are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate; therefore pro-survival mechanisms are critically important. Insulin like growth factor–II (IGF-II) is a potent survival and growth factor, however its major function is thought to be in prenatal development when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using in vitro and in vivo techniques we now show in man and mouse that the podocyte is the major cellular source of, and target for IGF-II in the mature glomerulus. Functionally a loss of IGF-II signaling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II knockout mouse deficient in IGF-II. Collectively this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.