Despite an increasingly understanding of the pathogenetic mechanisms of sepsis, its mortality remains extremely high, caused mainly by hemodynamic impairment-related alterations frequently present in severe sepsis. Currently, treatment of sepsis is based on hemodynamic support, antibiotic therapy, surgical excision of infectious foci and immunomodulatory therapy. In fact, a massive host inflammatory infection response has recently emerged to substantially contribute to the development of septic shock and multiple organ dysfunction. Many clinical trials on various pharmacological agents have been conducted: glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombin III (AT III), anti-endotoxin monoclonal antibodies, nitric oxide inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor (TNF) antibodies. Apart from some likely favourable findings connected to low doses of glucocorticoids, most studies yielded disappointing results. Nevertheless, the use of recombinant human activated protein C (drotrecogin-alpha) has recently proven to have a mortality reduction effect particularly in patients with severe sepsis and dysfunction of at least two organs. Furthermore, the early treatment of hemodynamic instability with volume expanders and vasopressors (early goal-directed therapy), and a strict glycemic control represent important measures in order to significantly reduce mortality from severe sepsis and septic shock, and are fundamental guidelines recommended by most scientific societies (Surviving Sepsis Campaign).