The immune system plays a dual role in the pathogenesis of sepsis and organ failure, intended for host defense but also possessing significant cytodestructive capacity. As the understanding of the epidemiology and pathophysiology of these disorders improves, so too does the appreciation for the complexity of this system. No longer is the immune response viewed as simply cellular or humoral but rather as a network of cells, chemical mediators, and molecular elements. The interactions between these various components serve to regulate and coordinate the inflammatory response. When this fine balance is lost, the inflammatory response becomes pathologic and self-destructive. Organ injury ensues, and with this injury, further escalation of the inflammatory response occurs; becoming a self-perpetuating process. Conventional therapy is limited to supportive care and has been ineffective in improving mortality. To date, efforts to modulate the inflammatory response by inhibition of specific components have been unsuccessful. In the future, better patient selection, combination therapy (perhaps using strategies of early augmentation followed by inhibition), and alternative techniques such as blood purification may prove to be more effective.