Pharmacological therapy of systolic left ventricular dysfunction has evolved over the past 3 decades. Current therapy is focused primarily on the regulation of the renin-angiotensin-aldosterone axis and sympathetic nervous system. Additional targets of pharmacotherapy include vasoconstriction, impaired nitric oxide metabolism, inflammation and improving myocardial function. As therapies in chronic systolic heart failure have evolved beyond diuretics and digoxin, so too has mortality improved. Future directions in the management of heart failure include cell-based and genetic therapy, and further refinement of current therapy through genetics.