Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic heart failure (HF) by influencing heart contractility, inducing hypertrophy and promoting apoptosis, contributing to myocardial remodeling. While several stimuli may be operating such as heat shock proteins, microbial antigens and oxidative stress, it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in HF regardless of the initial event. Traditional cardiovascular drugs appear to have little influence on the cytokine network, and immunomodulatory therapy has emerged as a possible new treatment modality in HF. Several animal studies and also some clinical studies have suggested that downregulation of inflammation may improve cardiac performance. However, the results from the placebo-controlled anti-tumor necrosis factor studies suggest no improvement or even adverse effects of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients resulting in beneficial net effects. Further research will have to identify more precisely the most important actors in the immunopathogenesis of chronic HF in order to develop more specific immunomodulating agents for this disorder.