Depression is a common co-morbid condition in patients with cardiac disease and has been identified as an independent risk factor for increased morbidity and mortality. SSRIs are established agents for the treatment of depression and are well tolerated in patients with cardiac disease. SSRIs are a heterogeneous group of antidepressants, which apart from their common mechanism of action, differ substantially in their chemical structure, metabolism and pharmacokinetics. This article reviews experimental and clinical evidence on the safety and efficacy of the most extensively studied SSRI, sertraline, in depressed patients with coronary artery disease and heart failure. Intervention with sertraline has the potential to provide depressed patients with cardiac disease relief from their depressive symptoms, improvement in quality of life and a potential benefit in their cardiovascular risk profile.