Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. Over the past decade, evidence has accumulated indicating that short-term insulin administration, in addition to its metabolic effects, also has important cardiovascular actions. The sympathetic nervous system and the L-arginine-nitric oxide pathway have emerged as central players in the mediation of insulin's cardiovascular actions. The underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant subjects. Here we summarize the current understanding and gaps in knowledge on insulin's cardiovascular actions in humans, and discuss possible pathophysiological consequences of their alteration. Based on recent new insight, we propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.