Despite advances in supportive care of critically ill patients, sepsis remains an important cause of death worldwide. More than 750,000 individuals develop severe sepsis in North America annually, with a mortality rate varying between 35 and 50%. Over recent years, numerous efforts have been committed to understanding the pathophysiology of septic syndrome, as well as attempts to intervene in the inflammatory cascade with the aim of altering the outcome of the syndrome and to improve survival. Not all of these attempts have been successful. Issued guidelines by the International Sepsis Forum have incorporated only the use of corticosteroids, tight glycemic control and the use of recombinant activated protein C as recommendations for the management of the septic patient along with the initial resuscitation and infection-site control measures. These strategies along, with novel attempts of immunomodulation, are thoroughly reviewed in this article.