Obesity and insulin resistance are reaching epidemic proportions worldwide. Over the past decade, nitric oxide (NO) has emerged as a key player in the regulation of the metabolic and cardiovascular homeostasis. Here we will review recent data obtained in mice with disruption of the genes encoding for each of the three nitric oxide synthase isoforms. These data demonstrate that both defective and augmented NO synthesis have detrimental effects on the regulation of the metabolic and cardiovascular system. These observations provide the rationale for the use of NO-donors and/or inhibitors of NO overproduction in the treatment of insulin resistance.