Obesity is an emerging problem worldwide. Hospitalized obese patients often have a worse outcome than patients of normal weight, particularly in the setting of trauma and critical care. Obesity creates a low-grade systemic inflammatory response syndrome (SIRS) that is similar (but on a much smaller scale) to gram-negative sepsis. This process involves up-regulation of systemic immunity, is characterized clinically by insulin resistance and the metabolic syndrome, and puts the patient at increased risk for organ failure, infectious morbidity, and mortality. Through lipotoxicity and cytokine dysregulation, obesity may act to prime the immune system, predisposing to an exaggerated subsequent immune response when a second clinical insult occurs (such as trauma, burns, or myocardial infarction). Specialized nutrition therapy for such patients currently consists of a hypocaloric, high-protein diet. However, this approach does not address the putative pathophysiologic mechanisms of inflammation and altered metabolism associated with obesity. A number of dietary agents such as arginine, fish oil, and carnitine may correct these problems at the molecular level. Pharmaconutrition formulas may provide exciting innovations for the nutrition therapy of the obese patient.