Evidence has steadily accumulated in favor of the use of nutritional supplements in the support of critically ill patients. The observed effects of nutrients on the immune and inflammatory response have led to the evolution of more sophisticated nutritional concepts and strategies in the critically ill. Acute critical illness is characterized by an accelerated and unbalanced catabolism of proteins, fat, and glycogen stores with the main impediment of physiological function related to protein loss. Protein stores are degraded by the body due to increased energy needs (caloric starvation), new protein needs (amino acids shortage for synthesis of acute phase proteins), hyper-glycosylation, and oxidation. Strategies to reduce protein breakdown include tight caloric supplementation, providing high biological protein supplementation, and avoiding high plasma glucose levels. However, basic nutritional support is only ameliorating, but not stopping the loss of total body protein mass observed in acute severe illness. Administration of immune-enhancing formulas supplemented with a combination of glutamine, arginine, omega-3 fatty acids, and nucleotides has been shown in many studies to improve infectious outcomes. Reducing inflammation and replenishing the body’s antioxidative stores is one of the main goals of nutritional supplementation in critically ill patients. Furthermore, enteral formulas enriched with arginine, nucleotides, glutamine, and omega-3 fatty acids are constantly being investigated in the context of trauma, ARDS, acute pancreatitis, and sepsis. In the present chapter we will focus mainly on substrates designed to diminish oxidative stress and on nutritional supplements aiming towards modulation of the immune system (pharmaco-nutrition).