Cardiac fibrosis occurs in response to numerous factors including ischemia, myocardial scarring after infarction, pressure overload of the heart, and a complex interplay of multiple hormonal systems. Transforming growth factor-beta (TGF-β) is a locally generated cytokine that participates in healing processes and tissue fibrosis following cardiac injury. TGF-β1 induces the proliferation of cardiac fibroblasts and their phenotypic transformation to myofibroblasts, and the deposition of extracellular matrix (ECM). This review examines current knowledge on TGF-β signal transduction pathways and the effects of TGF-β inhibition on the development of cardiac fibrosis. Improved understanding of the actions and signaling of this cytokine system may lead to the development of new therapeutic strategies that combat the development of myocardial fibrosis in the pathogenesis of heart failure.