Sepsis and septic shock continue to be a major cause of morbidity and mortality. Despite numerous advances in the supportive care of patients with sepsis, the overall mortality has changed little in the past 20 years. Many innovative therapies have been attempted in the field of sepsis, primarily aimed at stopping the cycle of cytokine activation which is part of the systemic inflammatory response. Therapies have also targeted other molecular mediators of inflammation and coagulation. Despite encouraging preliminary preclinical results, most of the early trials in sepsis research have failed to offer hope of improving survival with the use of these innovative therapies. Postulated reasons for the failure of clinical trials include the disparity between animal models and clinical reality, the heterogeneous nature of patient populations and sepsis, and the complexity of the inflammatory cascade. On a more hopeful note, three recent trials assessing corticosteroids, anti-tumour necrosis factor strategy and drotrecogin alfa (rhAPC), respectively, have proclaimed positive results. However, only the drotrecogin alfa trial has been peer reviewed and published.