Inflammation in the vasculature might be an important pathogenic link between cardiovascular diseases and the metabolic syndrome. Inflammation can be reduced by a variety of approaches including diet, exercise, cardiovascular drugs, and insulin sensitizers. Importantly, these different measures improve vascular function and reduce inflammation by distinct mechanisms. Therefore, combination therapy including lifestyle modifications and multiple drugs from separate classes might produce additive beneficial outcomes. We review plausible mechanisms for effects of combination therapy to reduce inflammation, improve endothelial dysfunction, and decrease insulin resistance in atherosclerosis, coronary heart disease, and hypertension in the context of insulin-resistant states including diabetes, obesity, and the metabolic syndrome.