Patients with heart failure undergoing non-cardiac surgery still have an unacceptably high morbidity and mortality. Compromised myocardial physiologic reserves in combination with extensive surgery and anesthesia appear to play a crucial role in determining high perioperative morbidity and mortality. Nevertheless, several other mechanisms and pathways such as metabolic factors, ischemia-reperfusion conditions, neurohormonal activation, inflammation and oxidative stress contribute to the adverse outcome. Several cardiovascular drugs have been investigated with the attempt to reduce the incidence of cardiovascular adverse events after major non-cardiac surgery. In the last years, increasing attention has been paid to the use of levosimendan in the perioperative period of patients undergoing cardiac surgery. As an inodilator, levosimendan - at low energy expenditure - may improve perioperative cardiac performance of heart failure patients by optimizing ventriculo-arterial coupling, rather than by increasing myocardial contractility itself. By its vasodilating properties, levosimendan may also improve systemic and regional blood flow. In addition to these hemodynamic properties, non hemodynamic effects of levosimendan may further improve microcirculation and organ function. At the cellular level in the heart, kidney, lung, liver as well as the gut, levosimendan exerts protective preconditioning effects secondary to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Taking into account these multiple but complementary mechanisms, levosimendan appears to be a suitable agent for preoperative optimization of cardiac functions in heart failure patients undergoing major elective surgery. Nevertheless, large-scale trials are needed before final conclusions can be drawn on the use of levosimendan in this indication.