Insulin-like peptides are an ancient acquisition in phylogeny, suggesting a crucial biological role for these family of peptides. Indeed, a key function of these hormones in cell metabolism and growth has been firmly established. However, their significance in neuronal physiology is less characterized, although progress in recent years on the neuroactive properties of insulin and insulin-like growth factor I (IGF-I) supports an important role for these hormones in brain function. During development, appropriate IGF-I input is critical in brain growth while the role of insulin at this stage, although not well defined yet, may be related to the control of neuronal survival. In the adult, IGF-I is a pleiotropic signal involved in numerous processes to maintain adequate brain cell functions, while the role of insulin is better known in relation to the control of food consumption and glucose metabolism. The potential involvement of IGF-I in brain diseases associated with neuronal death is strongly supported by its neuroprotective role. Further, the unexplained high incidence of glucose metabolism dysregulation in brain diseases makes also insulin a strong candidate in neuro-pathological research. Because mounting evidence suggests a complementary role of insulin and IGF-I in the brain, unveiling the cellular and molecular pathways involved in brain insulin/IGF-I actions is helping to establish potentially new therapeutic targets and its exploitation may lead to new treatments for a wide array of brain diseases.