Multiple organ dysfunction syndrome (MODS), characterized by the progressive dysfunction of vital organs and organ systems, remains a significant cause of morbidity and mortality in critically ill patients. MODS develops consequent to a maintained pathology resulting from a variety of insults including blunt trauma, tissue injuries and uncontrolled infections, the last often leading to sepsis and eventually shock. MODS is invariably associated with a systemic inflammatory response syndrome (SIRS) with its excessive expression and production of inflammatory mediators and cytokines whose actions are not adequately balanced by an anti-inflammatory response. The gastrointestinal tract often participates in the development and pathology of MODS, particularly if its blood flow is reduced thereby setting up the development of ischemia- reperfusion (I/R) injury. The intestine is also a source of pathogenic bacteria if mucosal integrity is compromised, and the subsequent infections set the stage for SIRS. The treatment for MODS remains a major clinical problem as a consequence of the complexity of the inflammatory response. Even though a reliable, effective treatment for MODS remains elusive new therapies and drugs are continually being developed and tested, such that its effective management may soon become a clinical reality.