Currently, only limited treatments are available for insulin resistance, a major cause of type 2 diabetes (T2D) and the metabolic syndrome. Combined innovative pharmaceutical and non-pharmaceutical strategies are needed. Obesity, a major cause of insulin resistance in T2D, can be treated relatively safely with modern bariatric surgery. Exercise training to increase VO(2max) is an important non-pharmaceutical approach to decrease insulin resistance. The thiazolidinediones are useful in treating insulin resistance, but newer agents with broader specificity might be more efficacious without deleterious side effects. Recently oxidative stress has been implicated in insulin resistance. One antioxidant that is safe and appears effective is alpha-lipoic acid. Thus, combinations of surgery, exercise training, insulin sensitizers and antioxidants will probably constitute future insulin resistance management.