Therapies that block the actions of interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-α) have been proposed to be potentially beneficial in critically ill patients with sepsis. Clinical trials demonstrated no survival benefit when the actions of IL-1 were blocked. In contrast, inhibition of TNF-α with either monoclonal antibodies or TNF receptor fusion proteins appeared to improve survival in prospectively defined groups of patients with severe sepsis, including those with dysfunction of two or more organ systems or with septic shock associated with the dysfunction of at least one organ system. Although none of the clinical trials has demonstrated statistically significant improvements in mortality for patients who received anticytokine therapy 28 days before, few of the completed studies were initially powered to achieve statistical significance at the day 28 end point. While the available data suggest that anti-TNF therapies improve survival in groups of patients with sepsis that can be identified by clinical criteria, confirmation of the potentially beneficial effects of anti-TNF agents awaits completion of the large multicenter clinical trials that are presently examining the utility of these therapies.