In the past two decades, major improvements in antibiotics and other elements of supportive care have decreased the number and severity of complications of hematopoietic stem cell transplantation (HSCT). Despite these improvements, many subpopulations of transplant patients still have a significant morbidity and mortality. It is becoming increasingly clear that medical science does not have a good understanding of the pathophysiology of many of the common, potentially fatal complications in patients currently undergoing HSCT. As the mechanisms of these complications are subjected to increasingly more rigorous scrutiny, it is becoming clear that many of these complications are intimately connected one to another and are not isolated clinical disorders as previously thought. One hypothesis that can explain the close relationship between them is that most of the severe complications of HSCT are the result of a systemic inflammatory disorder that has escaped biologic control, an inflammatory process begun by the preparative regimen and perhaps added to by intercurrent infections, tumor cell death and other as yet unidentified stimuli (transfusions, medications?). If this is true, this syndrome would have many similarities with the multiple organ dysfunction syndrome (MODS) seen in critically ill non-transplant patients. As such, this hypothesis has two significant corollaries: (a) That looking for or empirically treating for a reversible organ specific cause of single organ dysfunction during HSCT (such as infectious pneumonia, intracranial hemorrhage, or acute infectious hepatitis) in any given patient is unlikely to be rewarding as the defect causing the organ dysfunction is often systemic at the time of its presentation, and (b) that MODS is the dose-limiting toxicity of our current preparative regimens, suggesting that when we understand its pathophysiology and develop therapies for MODS we will be able to escalate their intensity and, by doing so, cure more patients of their malignancy. Manipulation of the hemostatic system may prove to be one of these therapies, but there is little doubt that other interventions designed to modulate the inflammatory process will prove to be even more useful in this syndrome. Using the definitions of organ dysfunction outlined in this article, we can provide a basis for clinical monitoring of patients today and for use in interventional clinical trials in the future.