Chronic heart failure is a complex disorder with interactions among the cardiovascular, immune, and neurohormonal systems. The concept that the progression of heart failure is due to neurohormonal abnormalities has received the greatest attention to date, leading to substantial therapeutic benefits. Although many current therapies are also thought to exert a variety of immunologic effects, this has been much less studied. In this review, the authors discuss a number of interactions among immune pathways and neurohormonal abnormalities relevant to heart failure. Cytokines, in particular tumor necrosis factor-α, have tremendous interactive opportunities within a regulatory network of energy metabolism, immune function, and neuroendocrine and hormonal function. Inflammatory cytokines are known to contribute to the progression of heart failure, and have been related to patients' prognosis. Advanced heart failure can be considered a state of chronic (low-grade) inflammation, and there are many reasons to suggest that anticytokine therapy could be successful in these patients. These novel approaches are certainly not without some risk, and many of them are very expensive, which may limit their application to certain subgroups of patients. In the future, it may not be enough to monitor cardiac function alone. Rather, the immune and neurohormonal status of patients may also need to be included in the performance of a complete assessment.