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 blood-stream. 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.