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Many performance-enhancing supplements and/or drugs are increasing in popularity among professional and amateur athletes alike. Although the uncontrolled use of these agents can pose health risks in the general population, their clearly demonstrated benefits could prove helpful to the critically ill population in whom preservation and restoration of lean body mass and neuromuscular function are crucial. Post-intensive care unit weakness not only impairs post-intensive care unit quality of life but also correlates with intensive care unit mortality. This review covers a number of the agents known to enhance athletic performance, and their possible role in preservation of muscle function and prevention/treatment of post-intensive care unit weakness in critically ill patients. These agents include testosterone analogues, growth hormone, branched chain amino acid, glutamine, arginine, creatine, and β-hydryoxy-β-methylbutyrate. Three of the safest and most effective agents in enhancing athletic performance in this group are creatine, branched-chain amino acid, and β-hydryoxy-β-methylbutyrate. However, these agents have received very little study in the recovering critically ill patient suffering from post-intensive care unit weakness. More placebo-controlled studies are needed in this area to determine efficacy and optimal dosing. It is very possible that, under the supervision of a physician, many of these agents may prove beneficial in the prevention and treatment of post-intensive care unit weakness.