Morbidity and mortality of cardiovascular disease (CVD) is exceedingly high worldwide. Depressive illness is a serious psychiatric illness that afflicts a significant portion of the world population. Epidemiological studies have confirmed the high co-morbidity between these two disease entities. The co-morbidity is bidirectional and the mechanisms responsible for it are complex and multifaceted. In addition to genetic, biological systems, psychosocial, and behavioral factors that are involved include the central and autonomic nervous systems, the neuroendocrine, immune, and the vascular and hematologic systems. Specific pathophysiologic factors across these systems include homeostatic imbalance between the sympathetic and the parasympathetic systems with loss of heart rate variability (HRV) in depression, sympathoadrenal activation, hypothalamic-pituitary-adrenal (HPA) axis activation, immune system dysregulation resulting in a pro-inflammatory status, platelet activation, and endothelial dysfunction. These abnormalities have been demonstrated in most individuals diagnosed with major depressive disorder (MDD), bipolar disorder (BPD), and probably in other psychiatric disorders. A likely common instigator underlying the co-morbidity between cardiovascular pathology and depression is mental stress. Chronic stress shifts the homeostatic balance in the autonomic nervous system with sustained sympathetic overdrive and diminished vagal tone. Diminished vagal tone contributes to a pro-inflammatory status with associated sequelae. Stress hormones and certain pro-inflammatory substances released by macrophages and microglia upregulate the rate-limiting enzymes in the metabolic pathway of tryptophan (TRP). This enzymatic upregulation stimulates the kynurenine (KYN) pathway resulting in the formation of neurotoxic metabolites. Inflammation occurs in cardiac, cardiovascular, and cerebrovascular pathology independent of the presence or absence of depression. Inflammation is closely associated with endothelial dysfunction, a preamble to atherosclerosis and atherothrombosis. Endothelial dysfunction has been detected in depression and may prove to be a trait marker for this illness. Thus understanding vascular biology in conjunction with psychiatric co-morbidity will be of critical importance. Antidepressant drug therapy is of definite benefit to patients with medical and psychiatric co-morbidity and may reverse the pro-inflammatory status associated with depression. There is, however, an urgent need to develop novel pharmacotherapeutic approaches to benefit a much larger proportion of patients suffering from these disease entities.