Over 24 million people in the U.S. have diabetes mellitus, and about 90% of these have the type 2 form of the disease. In addition, an estimated 40–60 million people have pre-type 2 diabetes, impaired glucose tolerance or the cluster of abnormalities referred to variably as the metabolic syndrome or syndrome X (Reaven 1988). In all of these disorders, a central component of the pathophysiology is insulin resistance. Insulin resistance is also closely linked to other common health problems, including obesity, polycystic ovarian disease, hyperlipidemia, hypertension and atherosclerosis (Biddinger and Kahn 2006). Recent data also indicate a link between insulin resistance, type 2 diabetes and Alzheimer’s disease (Craft 2007). Cross-sectional studies have suggested an association between type 2 diabetes and cognitive decline, especially in aspects of verbal memory (Strachan et al. 1997). Longitudinal studies have revealed that patients with type 2 diabetes have a 1.5-fold greater change over time in measures of cognitive function than those without diabetes (Cukierman et al. 2005). While some of this change may certainly be due to the increased prevalence of atherosclerosis in diabetic patients, there is increasing evidence that insulin resistance itself may affect CNS function and risk of Alzheimer’s disease. In this review we will explore this relationship, focusing on experiments we have performed in mice.