The purpose of the present paper is to provide a rationale for zinc supplementation as a potential therapeutic agent in critically ill patients by describing its role in health and disease, conducting a systematic review of current randomized trials in critical care, considering optimum route and dose of administration, and making recommendations for future research. Normal zinc homeostasis is required for a functional immune system, adequate antioxidant capacity, glucose homeostasis, and wound healing. In addition, zinc is a required cofactor for many enzymes, transcription factors, and replication factors. In non-critically ill patients, zinc supplementation has been associated with an improvement in markers of immune function. In critically ill patients, only 4 randomized trials have examined the effect of zinc supplementation on clinical outcomes. When all 4 studies were aggregated, zinc supplementation was associated with a nonsignificant reduction in mortality (relative risk = 0.63, 95% confidence intervals 0.25-1.59, P = .33) and length of stay in intensive care (-0.35 days, -0.85 to 0.15; P = .17). Thus, because of the paucity of clinical data, there is inadequate evidence to recommend the routine use of high-dose zinc supplementation in the critically ill. A first step would be to determine the optimal dose that has a maximal positive effect on underlying inflammatory, immunologic, and metabolic processes yet is safe and tolerated by critically ill patients. Subsequently, large, rigorously designed, randomized trials are required to elucidate the efficacy of such doses of zinc supplementation in this patient population.