Multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in intensive care units. It is being encountered frequently in critically ill patients owing to advancements in organ-specific supportive technologies to survive the acute phase of severe sepsis and shock. It is now believed that MODS is the result of an inappropriate generalized inflammatory response of the host to a variety of acute insults. The pathologic mechanisms of MODS were reviewed, and factors determining the sequence and severity of organ dysfunction were discussed in depth. In the early phase of MODS, circulating cytokines cause universal endothelium injury in organs. In the later phase of MODS, overexpression of inflammatory mediators in the interstitial space of various organs is considered a main mechanism of parenchyma injury. The difference in constitutive expression and the upregulation of adhesion molecules in vascular beds and the density and potency of intrinsic inflammatory cells in different organs are the key factors determining the sequence and severity of organ dysfunction. By activating the intrinsic inflammatory cell in a distant organ, organ dysfunctions are linked in a positive feedback loop through circulating inflammatory mediators. Antagonists targeted at adhesion molecules may alleviate the severity of endothelial damage. And nonsteroidial anti-inflammatory drugs or steroids administered judiciously in the early phase of MODS may retard the progress of multiple organ failure.