Insulin resistance of muscle glucose transport is a primary defect leading to the development of type 2 diabetes. One contributor to insulin resistance is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) acts on ANG II type 1 receptors in the vascular endothelium and in myocytes, enhancing the intracellular production of reactive oxygen species (ROS). Animal model and cultured skeletal muscle cell line studies indicate that ANG II induces insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces an insulin-resistant state associated with a negative impact of ROS on the muscle glucose transport system. ANG II treatment of L6 myocytes impairs IRS-1-dependent insulin signaling that is accompanied by augmented NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole-body and muscle insulin resistance associated with local oxidative stress and significant reductions in the functionality of the IR/IRS-1-dependent insulin signaling. Treatment with ANG II type 1 receptor antagonists leads to improvements in whole-body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole-body and muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. These findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with pre-diabetes and type 2 diabetes.