Sepsis is a clinical syndrome that results from a systemic host response to an infection. The outcome of sepsis is poor, and mortality rates are as high as 30-40%. Sepsis is associated with the activation of multiple inflammatory pathways, including the cytokine network and the coagulation system. Sepsis can also result in an immunodepressed state that could leave patients more susceptible to secondary nosocomial infections. Modulation of the host response to infection has been studied as an adjunctive therapeutic approach in many preclinical investigations and clinical trials in the past 20 years. As a result of these studies our knowledge of the pathogenesis of sepsis has increased considerably. This review focuses on immunomodulatory strategies that have reached the phase of clinical evaluation in patients with sepsis.