Evaluating protein kinetics in the critically ill population remains a very difficult task. Heterogeneity in the intensive care unit (ICU) population and wide spectrum of disease processes creates complexity in assessing protein kinetics. Traditionally, protein has been delivered in the context of total energy. Focus on energy delivery has recently come into question, as the importance of supplemental protein in patient outcomes has been shown in several recent trials. The ICU patient is prone to catabolism, immobilization, and impaired immunity, which is a perfect storm for massive loss of lean body tissue with a unidirectional flow of amino acids from muscle to immune tissue for immunoglobulin production, as well as liver for gluconeogenesis and acute phase protein synthesis. The understanding of protein metabolism in the ICU has been recently expanded with the discovery of how the mammalian target of rapamycin complex 1 is regulated. The concept of “anabolic resistance” and identifying the quantity of protein required to overcome this resistance is gaining support among critical care nutrition circles. It appears that a minimum of at least 1.2 g/kg/d with levels up to 2.0 g/kg/d of protein or amino acids appears safe for delivery in the ICU setting and may yield a better clinical outcome.