The multiple organ dysfunction syndrome is a common but poorly understood complication of critical illness. Its evolution reflects the interactions of an acute, life-threatening insult, the response of the host to that insult, and the therapeutic measures instituted to restore normal homeostasis. Although the cellular mechanisms remain elusive, processes such as inflammation, microvascular thrombosis, apoptosis, and fibrosis and tissue repair contribute to its clinical expression. In the lung, these forces create the characteristic changes of ARDS; that common disorder, however, is better seen as one manifestation of a systemic process than as an isolated problem of the lung. Therapy, in the absence of a more sophisticated understanding of pathologic mechanism, is supportive. The growing recognition that iatrogenic factors contribute to the expression of MODS has highlighted the need for the clinician to be aware of the potential for harm inherent with every intervention.