Depression and heart disease are commonly comorbid. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression. In March 2011, we carried out a 15-year search of PubMed for preclinical and clinical publications related to SSRIs and ischemic heart disease (IHD) or congestive heart failure (CHF). We identify and discuss a number of mechanisms by which SSRIs may influence cardiovascular functioning and health outcomes in patients with heart disease; many of the mechanisms that we present have received little attention in previous reviews. We examine studies with positive, neutral, and negative outcomes in IHD and CHF patients treated with SSRIs. SSRIs influence cardiovascular functioning and health through several different mechanisms; for example, they inhibit serotonin-mediated and collagen-mediated platelet aggregation, reduce inflammatory mediator levels, and improve endothelial function. SSRIs improve indices of ventricular functioning in IHD and heart failure without adversely affecting electrocardiographic parameters. SSRIs may also be involved in favorable or unfavorable drug interactions with medications that influence cardiovascular functions. The clinical evidence suggests that, in general, SSRIs are safe in patients with IHD and may, in fact, exert a cardioprotective effect. The clinical data are less clear in patients with heart failure, and the evidence for benefits with SSRIs is weak.