Despite advances in the understanding of pathophysiological mechanisms, there are limited pharmacotherapeutic options for sepsis, septic shock, and related pathologies. It is surprising that although sepsis-induced myocardial depression is documented in clinics, the cellular mechanisms are from clear. Alterations in molecular signaling mechanisms activated by cytokines and potent mediators such as ET-1 could pose the risk for myocardial dysfunction in sepsis. Our laboratory data suggest that the septic heart, in vivo, exhibits an increased time constant of left ventricular relaxation, tau, along with changes in LVEDP. We also observed that bigET-1-induced elevation of ET-1 correlates with cardiodynamic alterations, induction of apoptosis, and activation of p38-MAPK phosphorylation during sepsis. In light of these evidences, we emphasize that these molecular alterations in heart, both at organ and cellular level during early sepsis, need to be elucidated thoroughly.