Insulin-like growth factor I (IGF-I) is present at high concentrations in the circulation. Tissue-specific genetic ablation has shown that the majority of serum IGF-I is secreted by liver cells, although all major organs synthesize it. IGF-I is an important signal during development, including brain growth. Although the biological role of IGF-I in organs such as muscle or ovary is reasonably well established, its biological significance in the adult brain is far from clear. In this regard, while local IGF-I synthesis decreases during brain development, protein levels remain relatively constant throughout life until old age, where a decline is found, not only in the brain but also in the bloodstream. This mismatch between declining local synthesis early after birth and steady protein levels may be explained by the ability of serum IGF-I to access the brain across the blood-brain-barrier. This peripheral IGF-I input to the brain is a physiologically meaningful process of potential impact in brain diseases. Numerous brain mechanisms are regulated by serum IGF-I. Many of these, such as cell energy modulation or growth and survival are common to other IGF-I target tissues but there are also a number of brain-specific mechanisms regulated by IGF-I which likely underlie the ability of serum IGF-I to modulate the major function of the brain: cognition. We propose that serum IGF-I forms part of the mechanisms involved in the "cognitive reserve" concept of brain responses to homeostasis breakdown. Based on IGF-I pleiotropy not only in brain but elsewhere, we consider that loss of IGF-I function is an important step towards disease.