The addition of immune-modulating nutrients to enteral formulas has been examined in clinical trials and meta-analyses. Enhancing immunity through diet is generally done by adding n-3 fatty acids, arginine, and nucleotides to an otherwise nutritionally complete formula. Despite flaws in many studies, a consistent trend to reduced infectious complications has been seen with immunonutrition, especially in patients undergoing surgery for upper gastrointestinal cancer or trauma. In critical care populations, however, the results have been mixed. In this review, we analyze these studies and focus on select clinical points that may explain the variation. One common flaw has been a failure to deliver an adequate nutrition volume. Few patients, especially in the earliest studies, received even close to goal feeding. A minimum quantity of immunonutrition may be required for effective reduction in infections. When feeding volumes are low, immunonutrition is usually not better than an isonitrogenous control. In more recent studies, practitioners have been increasingly aggressive with enteral feeding, and this has been reflected in improved outcomes from immunonutrition. Early delivery of immunonutrition (preoperatively in surgical patients with cancer) might be particularly beneficial. Another consideration is illness severity: we discuss evidence that the use of immunonutrition in moderate illness is more likely to be helpful, whereas severe sepsis is probably beyond the reach of any nutritional intervention, and mild illness is more likely to improve irrespective of feeding. If future trials can consider these vital points, level 1 recommendations in favor of immunonutrition might be justified, although presently such evidence is lacking for most clinical indications.