Diabetes has become a national and international epidemic with the incidence of diabetes expecting to double by the year 2030. The metabolic and structural abnormalities observed in diabetic patients, in patients with the metabolic syndrome, and now being observed in the post-surgical intensive care unit, have all been associated with the development of endothelial dysfunction. Recent studies suggest that this finding of endothelial dysfunction may be due to decreased bioavailability of a key signaling molecule, nitric oxide (NO), which is due to disruption of the endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase/cyclic guanosine monophosphate (cGMP)-dependent pathway. Disruption of this pathway results in an oxidative and nitrosative stress state that accelerates the progression and the complications of cardiovascular disease found in diabetes. The purpose of this chapter is to review current information about the disruption of this important signaling system especially in the context of diabetes.