Insulin resistance is a characteristic feature of Type 2 diabetes mellitus and obesity. Although defects in glucose homeostasis have been recognized for decades, the molecular mechanisms accounting for impaired whole body glucose uptake are still incompletely understood. This lecture will focus on the sites of insulin resistance in Type 2 diabetes and mechanisms by which exercise enhances glucose uptake in skeletal muscle. Epigenetic modifications are thought to play an important role in the development of metabolic diseases. DNA methylation is one form of epigenetic modification linking environmental factors to the control of insulin sensitivity. The first part of this lecture will focus on the role of DNA methylation and insulin sensitivity in type 2 diabetes and obesity. Thereafter, the role of DNA methylation as a regulatory mechanism for gene expression changes in response to exercise will be discussed. Given the importance of lifestyle factors in the development of metabolic disorders, DNA methylation provides a mechanism by which environmental factors, including diet and exercise, play a role on the pathogenesis of skeletal muscle insulin resistance and risk for Type 2 diabetes.