Increased circulating and intracardiac levels of proinflammatory cytokines have been associated with chronic heart failure. Following an initial insult, the increased production of proinflammatory cytokines, including TNF-α, IL-6, IL-1, and IL-18, jeopardizes the surrounding tissue through propagation of the inflammatory response and direct effects on the cardiac myocyte structure and function. Cardiac myocyte hypertrophy, contractile dysfunction, cardiac myocyte apoptosis, and extracellular matrix remodeling contribute enormously to the development and progression of chronic heart failure. Despite the identification of efficacious pharmacological regimens and introduction of mechanical interventions, chronic heart failure remains among the leading causes of mortality worldwide. To introduce novel therapeutic strategies that modulate the inflammatory response in the context of the failing heart, it is of prime importance to determine the contributions of TNF-α, IL-6, IL-1, and IL-18 in mediating cardiac adaptive and maladaptive responses, as well as delineating their downstream intracellular signaling pathways and their potential therapeutic implications.