Experimental evidence is accumulating implicating a major role for inflammatory activation in chronic heart failure. Levels of pro-inflammatory protein mediators, such as tumor necrosis factor-alpha (TNF-α), a pro inflammatory cytokine, have been shown to be elevated in heart failure patients and appear to be directly related to pathological changes in the myocardium. Unfortunately, outcomes from clinical trials using anti-cytokine therapies to chronic heart failure patients have been largely disappointing. TNF-α is a pleiotropic cytokine, impacting tissues in a complex manner that regulates many physiological and pathological processes that can trigger differentiation, inflammation, and cell death. TNF-α is important in initiating and regulating the cytokine cascade during an inflammatory response. Most of the studies focused on the TNF-α as an immune mediator but its function in cardiac cells is not well defined. This review focuses on the role of TNF-α in acute and/or chronic cardiac conditions. We will discuss the problem with the current anti-cytokine therapies and potential problems underlying their lack of success so far.