Heart disease is among the leading causes of death in all populations. Cardiac dysfunctions are major complications in patients with advanced viral or bacterial infection, severe trauma and burns accompanied with multiple organ failure – collectively known as systemic inflammatory response syndrome (SIRS). SIRS, which is often subsequent to sepsis, is clinically featured by hypotension, tachypnea, hypo- or hyperthermia, leukocytosis and myocardial dysfunction. The striking association between inflammation and cardiac dysfunction not only prognoses likelihood of survival in patients with SIRS but also prompts the necessity of understanding the pathophysiology of cardiac dysfunction in SIRS, so that effective therapeutic regimen may be identified. Compelling evidence has shown significant and independent link among inflammation, sepsis, insulin resistance and cardiac dysfunction. Several cytokine signaling molecules have been speculated to play important roles in the onset of cardiac dysfunction under SIRS including endothelin-1 and toll-like receptor. Involvement of these pathways in cardiac dysfunction has been convincingly validated with transgenic studies. Nevertheless, the precise mechanism of action underscoring inflammation-induced cardiac contractile dysfunction is far from being clear. Given the substantial impact of inflammation and SIRS on health care, ecosystems and national economy, it is imperative to understand the cellular mechanisms responsible for cardiac contractile dysfunction under inflammation and sepsis so that new and effective therapeutic strategy against such devastating heart problems may be developed.