In human body metabolism, proteins and amino acids are required for the provision of (conditionally) indispensable amino acids, endogenous protein synthesis, and synthesis of signaling substrates and biogenic amins. While there exists balance in protein synthesis and degradation pathways in healthy conditions, critical illness is characterized by substantial immunologic, inflammatory, endocrinologic, and metabolic changes leading to extensive protein catabolism. In general, the catabolic state during critical illness is a result of decreased muscle protein synthesis by simultaneously increased muscle protein breakdown, synthesis of acute phase proteins, and energy production from glucoplastic amino acids. In consequence, the latter leads to negative nitrogen balance, depletion in single amino acids, profound loss of skeletal muscle mass, and increased risk for the development of an intensive care unit acquired weakness (ICUAW). In general, if left unattended and untreated, extensive catabolism during critical illness and concomitant clinical symptoms may lead to overall worse mid- to long-term clinical and functional outcome. In this context, adequate phase- and disease-specific protein/amino acid supply within an energy balanced medical nutrition therapy approach, targeted physical rehabilitation, and appropriate monitoring of protein/amino acid metabolism throughout the patients’ stay at an intensive care unit represent integral elements of medical treatment. Besides basic knowledge with regard to proteins/amino acids, this chapter provides an overview of current guideline recommendations on protein/amino acid supply in critically ill patients, recent evidence from clinical trials, and methods applicable for evaluating protein metabolism in routine clinical practice.