Insulin is the most abundant peptidergic hormone secreted by the pancreatic islets of Langerhans and plays an important role in organic metabolism. In recent years, various functions for insulin receptor signaling in the brain have been suggested in normal neurophysiology, and a dysregulation of insulin secretion or insulin receptor signaling has been reported in serious mental illnesses. Several lines of work in both laboratory animals and humans suggest that when neurons in cognitive brain regions such as the hippocampus and cerebral cortex do not make enough insulin or cannot respond to insulin properly, everything from very mild memory loss to severe neurodegenerative diseases can result. On the other hand, administration of insulin exerts memory-enhancing action in both humans and experimental animals. Insulin has also recently been shown to regulate the endocytosis of 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, which causes long-term depression (LTD) of excitatory synaptic transmission. The fact that LTD in the mammalian brain is generally assumed to be a synaptic mechanism underlying learning during novel experiences, this insulin-induced LTD may therefore serve as an important role in brain information processing. Recent advances in the knowledge of the biological role of brain insulin receptor signaling in relation to synaptic plasticity and cognitive function, and of the regulatory signaling mechanisms involved in these processes will be discussed in the article.