Diseases leading to critical illness induce proteolysis resulting in muscle wasting and negative nitrogen balance. Muscle wasting has been associated with poor intensive care unit (ICU)–related outcomes, including an increased risk for mortality. Acute kidney injury (AKI) represents a common organ dysfunction associated with ICU-related disorders, such as sepsis, trauma, and respiratory failure. AKI and renal replacement therapy lead to amino acid loss. Decompensated liver cirrhosis (DLC) and acute liver failure (ALF) represent more severe forms of liver dysfunction leading to ICU admission. DLC and ALF are associated with proteolysis and amino acid loss. AKI, DLC, and ALF uniquely contribute to negative nitrogen balance. The purpose of this review is to outline proteolysis associated with critical illness; define specific protein abnormalities in AKI, DLC, and ALF; define protein requirements in AKI, DLC, and ALF; and discuss barriers associated with optimal protein supplementation in these disorders.