Heart failure (HF) is a complex syndrome characterized by the inability of the heart to maintain a normal cardiac output without elevated intracardiac filling pressures, resulting in signs of pulmonary and peripheral edema and symptoms of dyspnea and fatigue. Central to the management of HF is a multifaceted pharmacological intervention to abate the harmful counter-regulatory effects of neurohormonal activation and avid salt and water retention. Whereas up to 40 years ago HF was managed with diuretics and leaf of digitalis, the cornerstones of therapy for HF patients with systolic dysfunction now include ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers), β-adrenoceptor antagonists (β-blockers), and aldosterone antagonists, which have significantly improved survival. However, with the increasing number of beneficial therapies, there are challenges to implementing all of them. Specific cardiomyopathies also merit specific considerations with respect to treatment, and - unfortunately - there is no therapy for HF with preserved left ventricular ejection fraction that has been shown to improve survival. Although mortality has improved in HF, the biggest challenge to treatment lies in addressing the morbidity of this disease, which is now the most common reason for hospital admission in our aged population. As such, there are many therapies that may serve to improve the quality of life of HF patients. Future HF treatment regimens may include direct cellular therapy via hormone and cytokine signaling or cardiac regeneration through growth factors or cell therapy.