Positive inotropic agents play an important role in the management of acute decompensated heart failure (HF) patients with reduced cardiac output and poor end-organ perfusion. However, despite their acute hemodynamic benefits, the role of inotropes in the management of chronic advanced HF remains limited. Although digoxin has demonstrated the ability to improve symptoms in HF patients, numerous small, mostly nonrandomized studies have shown that patients with advanced HF improve symptomatically when administered continuous or intermittent intravenous β-agonists or phosphodiesterase inhibitors. However, this improvement occurs at the expense of an increased risk of cardiac arrhythmias, sudden cardiac death, and mortality. Similarly, several oral inotropes have been developed and studied in larger randomized clinical trials. The PROMISE study found that oral milrinone is associated with increased mortality, whereas the ESSENTIAL study showed that oral enoximone does not result in any significant improvement in symptoms, exercise capacity, or survival. The calcium-sensitizing inotrope levosimendan has shown some promise in the management of acute HF patients, but the PERSIST trial showed no improvement in survival or hospitalization rates with chronic oral therapy. This agent is still under investigation and is not available in the United States. Istaroxime, an inotrope with lusitropic properties, is also being investigated for its potential use in advanced HF patients. The current American College of Cardiology/American Heart Association, European Society of Cardiology, and Heart Failure Society of America guidelines indicate that, other than digoxin, inotropic agents should be reserved for patients presenting with acute decompensated HF and low-output states and reduced end-organ perfusion, who typically are admitted to an intensive care unit. These agents also are of benefit in advanced HF patients as a bridge to transplantation to optimize end-organ function and may be used in the outpatient setting, usually in patients with an implantable cardioverter–defibrillator. Finally, inotropes should be used to palliate symptoms in end-stage HF patients who have severe symptoms and are not candidates for heart transplantation or mechanical circulatory support.