Sepsis, a progressive immunological, metabolic and cardiovascular disorder, is a major cause of morbidity and mortality in Intensive care units (ICU) worldwide. Models simulating sepsis, such as endotoxemia, peritonitis, cecal ligation and puncture, provide substantial molecular and cellular evidence for structural and functional damage to cardiac myocytes during sepsis. Clinical evidence suggests abnormal left ventricular impairment and cardiac contractile dysfunction during sepsis. Norepinephrine (NE), a clinically approved positive inotrope traditionally used in ICUs for hemodynamic support, can also cause increased lactate levels and cardiomyocyte toxicity during early stages of sepsis. Our recent results demonstrated that sepsis-induced myocyte dysfunction (SIMD) is associated with decreased time of deformation and loss of contractile activity in the myocytes. The data further support the involvement of the apoptotic pathway, particularly mitochondrial-mediated intrinsic apoptosis cascade in sepsis-induced myocardial dysfunction. The recent data from our laboratory demonstrated that SIMD is a potentially life threatening event which can be exacerbated by the use of positive inotropes such as NE, which are ideally used in the management of sepsis. © 2011 Bentham Science Publishers.