Chronic heart failure (CHF) is a growing health problem in developed nations. The pathological accumulation of extracellular matrix is a key contributor to CHF in both diabetic and nondiabetic states, resulting in progressive stiffening of the ventricular walls and loss of contractility. Proinflammatory disease processes, including inflammatory cytokine activation, contribute to accumulation of extracellular matrix in the heart. Transforming growth factor-? is a key profibrotic cytokine mediating fibrosis. Current therapeutic strategies do not directly target the profibrotic inflammatory processes occurring in the heart and hence there is a clear unmet clinical need to develop new therapeutic agents targeting fibrosis. Accordingly, strategies that inhibit proinflammatory cytokine activation and pathological accumulation of extracellular matrix (ECM) provide a potential therapeutic target for prevention of heart failure. This review focuses on the therapeutic targeting of TGF-? in the prevention of pathological fibrosis in the heart.