Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules termed cytokines, are also expressed in the setting of heart failure. This article will review recent clinical and experimental material which suggests that tumor necrosis factor (TNF), a pro-inflammatory cytokine, may contribute to disease progression in heart failure by virtue of the direct toxic effects that this molecule exerts on the heart and circulation.