In the Western hemisphere, the incidence of insulin resistance and its complications has been growing rapidly and is reaching epidemic proportions. Over the past decade, evidence has accumulated, indicating that nitric oxide (NO) plays a key role in the regulation of metabolic and cardiovascular homeostasis. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes insulin resistance, arterial hypertension and dyslipidemia in mice, and characterizes insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction in mice, may also cause metabolic insulin resistance, suggesting a Yin-Yang effect of NO in the regulation of glucose homeostasis. Here, we will review the evidence for this novel concept, and thereby provide the conceptual framework for the use of NO-delivery drugs and pharmacological agents that modulate the bioavailability of endogenously produced NO for the treatment of insulin resistance.