Some antidepressant agents can cause electrophysiological changes of cardiac function leading to ventricular arrhythmias and sudden death. However, antidepressants have also protective effects on the heart through their capacity to modulate cardiac autonomic-mediated physiological responses. Heart rate variability and QTc length are two strictly linked parameters that allow us to appreciate the effects of different drugs on cardiac physiology. Heart rate variability reflects functioning of the autonomic nervous system and possibly also regulation by the limbic system. Autonomic regulation of cardiac activity influences also cardiac repolarization and QT length, both directly and via its effects on heart rate. In this review we present the methodologies adopted to study the effect of antidepressant drugs on QT length and heart rate variability and we summarize data on electrophysiological changes related to antidepressant treatment. Clinical implications for the choice of different antidepressants in different clinical populations are discussed.