The consequences of depression and coronary artery disease (CAD) were reviewed in the literature. The comorbidity of depression and CAD results in an increased cardiovascular mortality. We reviewed possible explanations for this increased morbidity, which include: toxicity of tricyclic antidepressants that can cause cardiac arrhythmias, abnormalities in platelet function leading to increased platelet aggregation due to abnormalities in serotonin in the platelet (an abnormality that possibly causes depression in the central nervous system), diffuse atherosclerosis causing central nervous system abnormalities including depression (vascular depression), as well as the possibility that depressed patients are less compliant with their medications and physician-directed health recommendations. Recent reports of selective serotonin reuptake inhibitors (SSRIs) causing a reduced cardiovascular mortality may be related to serotonin platelet abnormalities in depressed patients that are effectively treated by SSRIs (SADHART and ENRICHD trial). It is possible that these trials reveal a mechanism of depression that also effects platelet function and can be improved with SSRI therapy, suggesting a preferential therapeutic pathway for the treatment of depressed patients with CAD.