Although considerable progress has been made in the pharmacologic and device management of chronic heart failure in recent decades, heart failure patients continue to remain symptomatic, with high hospitalization and mortality rates. A number of novel agents, including endothelin antagonists and tumor-necrosis factor blockers, have recently failed to improve the clinical outcomes of patients with heart failure. Have we reached a ceiling in preventing the progression of the disease? This article reviews successes and late-stage clinical trial disappointments in the treatment of patients with heart failure. Furthermore, the article discusses how agents that have beneficial effects in heart failure also generally attenuate or reverse ventricular remodeling, whereas the newer agents that have failed to improve clinical outcomes either had no effect on remodeling or have been associated with adverse remodeling.