Cardiovascular disease (CVD) is the leading cause of death and disability in the industrialized world, and the prevalence is increasing rapidly among developing nations. The rising prevalence of CVD worldwide may be attributed in large part to specific atherogenic changes in insulin resistance, adiposity, lipid profiles, and other indices of insulin resistance syndrome (IRS), a cluster of metabolic and hemodynamic abnormalities that are strongly predictive of CVD. A growing body of research suggests that chronic psychosocial stress and related factors significantly contribute to the pathogenesis of IRS-related abnormalities, associated insulin-resistant states, and CVD, in part by promoting dysregulation of the sympathoadrenal system and hypothalamic-pituitary-adrenal axis. In this article, we review the literature supporting the relationships between these factors, outline the neurophysiologic responses to chronic stress, and discuss the pathways by which chronic or recurrent psychosocial stress may lead to a destructive cascade of neuroendocrine, metabolic, inflammatory, and neuropsychological changes that fosters the development of IRS and, ultimately, CVD.