Recent investigations have shown that, in addition to neurohormonal system overactivation, another class of biologically active molecules, termed cytokines, is also overexpressed in the setting of chronic heart failure and participates actively in the progression of the syndrome. In this article, we present recent experimental and clinical data describing the pathophysiological role of cytokines in left ventricular remodeling, endothelial dysfunction, and peripheral myopathy characterizing the progression of chronic heart failure, as well as novel therapeutic approaches aimed at attenuating the deleterious effects of cytokines on the cardiovascular system.