Multiple organ failure, multiple organ dysfunction syndrome, and the systemic inflammatory response syndrome are problems of medical progress and intensive care units (ICUs) and require prevention of organ failure through excellent patient care. New concepts in prevention include: 1) the need to improve microcirculatory blood flow (Mbf) early after injury or illness, 2) stopping or controlling injury or infection by early definitive operation when necessary, 3) a zero defect operation is necessary, 4) necrotic tissue and an overwhelming inflammatory burden are problems and should be lessened when possible, 5) adequate resuscitation to improve Do2, Vo2, and organ blood flow is necessary, 6) supporting metabolism and the Gl tract may decrease complications of injury and sepsis, 7) support of host defense and/or immunomodulation to decrease the incidence of sepsis, and 8) treating the patient and the illness or injury, not just the mediators. Experimental evidence in animals and human volunteers for concepts, mechanisms, and treatment of injury or illness can be substantial and persuasive, but it may be difficult to demonstrate efficacy in sick patients. Clinical situations are variable and complex. It is difficult to dissect out, identify, and control or block a single factor or mediator. All biologic processes require a level of activity that can be hazardous in excess but dangerous if decreased or eliminated. Stimulation of our natural defense or control mechanisms of inflammation, replacement of lost or decreased factors, and better understanding of the interrelationships and mechanisms of inflammation will contribute to therapy. Whether blockade of mediators or treatment of the manifestations of diseases or injuries will have substantial impact remains to be learned. A single magic bullet for complex and diverse illnesses is not likely to appear or to be successful. In this review it was not possible to describe many of the observations and recommendations in this immense and complex field. I apologize to those whose work I have inadvertently not included.