The precise value of the normal adult protein requirement has long been debated. For many reasons—one of them being the difficulty of carrying out long-term nutrition experiments in free-living people—uncertainty is likely to persist indefinitely. By contrast, the controlled environment of the intensive care unit and relatively short trajectory of many critical illnesses make it feasible to use hard clinical outcome trials to determine protein requirements for critically ill patients in well-defined clinical situations. This article suggests how the physiological principles that underlie our understanding of normal protein requirements can be incorporated into the design of such clinical trials. The main focus is on 3 principles: (1) the rate of body nitrogen loss roughly predicts an individual’s minimum protein requirement and is thus essential to measure to identify individual patients and clinical situations in which the minimum protein requirement is importantly increased, (2) existing muscle mass sets an upper limit on the rate at which amino acids can be mobilized from muscle for transfer to central proteins and sites of injury and is thus important to monitor to identify patients who are at greatest risk of protein deficiency–related adverse outcomes, and (3) negative energy balance increases the dietary protein requirement, so calorie-deprived patients—whether obese or not—should be enrolled in hard clinical outcome trials that compare the current practice of “permissive underfeeding” (underprovision of all nutrients, including protein) with hypocaloric nutrition supplemented by a suitably generous amount of protein.