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Objective To perform a systematic review on previous trials of immunomodulatory therapies, on current therapies trialed previously and on potential therapies for the near future. Data analysis Electronic medical research databases were searched from 1950 or from the starting date of each database. The search was performed on 1 December 2013 and included earlier-published printed articles without language restrictions. Study selection The initial search presented 363 articles, of which 30 met the inclusion criteria. The articles were previous trials of immunomodulatory therapies as well as current therapies trialed previously and potential therapies for the near future. Data extraction The study quality aimed at achieving ethical approval, prospective design, specified eligibility criteria, the use of appropriate controls, adequate follow-up and defined outcome measures. Data synthesis Because of the heterogeneity in follow-up periods and reported outcome measures, it was not possible to pool the data and perform a meta-analysis. Comparisons were made by a structured review. Recent findings Numerous trials have been targeted at inhibiting various essential inflammatory mediators and receptors involved in sepsis. This includes the use of activated protein C, corticosteroids, statins and the inhibition of nitric oxide. Hypertonic saline solution, intravenous immunoglobulins, mesenchymal stem cells and colony-stimulating factors have also been tried. Corticosteroids and activated drotrecogin alfa are to date the only drugs that have demonstrated mortality benefits in large randomized controlled trials. Conclusion Our knowledge of the pathophysiology of the inflammatory response in sepsis continues to expand. Potential new therapies continue to be developed. Enhanced knowledge of the molecular biology of inflammation may result in improved treatment for septic patients.