Insulin, long known as an important regulator of blood glucose levels, plays important and multifaceted roles in the brain. It has been reported that insulin is an important neuromodulator, contributing to several neurobiological processes in particular energy homeostasis and cognition. Dysregulation of insulin signaling has been linked to aging and metabolic and neurodegenerative disorders. The first part of this review is devoted to discussion of the critical role of insulin signaling in normal brain function. Then the involvement of impaired insulin signaling in the pathophysiology of diabetes, Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis will be discussed. Finally, the potential therapeutic effect of insulin and insulin sensitizers will be examined.