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As a host systemic response to invasion of microbial pathogens into bloodstream, “Sepsis” has been considered as one of the leading cause of death in critically ill patients especially for the patients hospitalized in the Intensive Care Units of the developing countries. Approximately, 250,000 people succumb from sepsis in the USA, annually and almostly 2% of them are reported as severe septic patients with often bacterial resource. Pneumoniae, abdominal and urinary infections are most common types of clinical manifestations in mentioned patients. Common therapeutic strategies for sepsis are: supportive treatments, revised nutritional regimens, surgery of inflamed site and antibiotic therapy. On the one hand, these approaches have not been definitely beneficial for all cases, yet. On the other hand, indiscriminate usage of antimicrobial drugs, antibiotic resistance, predisposition infections or genetic composition of patients, reappearance of invasive pathogens with chronic incubation period and changing nature of clinical manifestations of the disease, all are inevitable barriers that make clinical diagnosis and treatment, inaccessible. These issues encourage basic medical scientists to put up with a barrage of questions in order to conduct investigations and more focus on comprehensive attitudes related to sepsis immune-pathophysiology. It seems that it is rational to adhere such principles in order to diminish organ failure and mount concerns over sepsis related mortalities of such global crisis.