Neuroplasticity is a concept that can be broadly defined as the ability of the central nervous system (CNS) to respond and adapt to the surrounding milieu. Neuroplasticity occurs in a variety of ways, including changes in the structural and functional properties of neuronal and non-neuronal cells as well as alterations in receptor pharmacology and neurochemical profiles. Ultimately these changes affect cognitive performance. Emerging evidence from clinical and preclinical studies suggests that insulin is an important mediator and facilitator of neuroplasticity in the CNS. Insulin administration improves cognitive performance in a variety of clinical settings ranging from normal healthy volunteers to patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Since the cognition-enhancing actions of insulin are likely mediated by insulin receptors (IR), these data suggest that impairments in the functional activities of insulin in the hippocampus may contribute to cognitive deficits observed in diabetes patients. The clinical and epidemiological data illustrate that diabetes patients have an increased risk of developing age-related disorders like AD, suggesting that deficits in IR signaling may be a key initiating factor in the development and progression of cognitive decline. An important question that remains to be addressed is the identification of the mechanisms through which insulin enhances cognitive performance and, conversely, how impairments in IR signaling may contribute to neuroplasticity deficits associated with diabetes and age-related disorders. This aim of this review is to discuss the literature that supports the hypothesis that insulin is a trophic factor in the CNS that supports neuroplasticity, particularly as it relates to how deficits in IR signaling may be a mechanistic link between neurological co-morbidities like AD and diabetes.