Clinical response to medication can differ between patients. Among the known sources of variability is an individual's nutrition status. This review defines some pharmacokinetic terms, provides relevant body size metrics and describes the physiologic influences of protein–energy malnutrition and obesity on drug disposition. Weight-based drug dosing, which presumes a healthy BMI, can be problematic in the protein–energy malnourished or obese patient. The use of total body weight, lean body weight, or an adjusted body weight depends on the drug and how it is differently handled in malnutrition or obesity. Most of the recognized influences are seen in drug distribution and drug elimination as a result of altered body composition and function. Distribution characteristics of each drug are determined by several drug-related factors (e.g. tissue affinity) in combination with body-related factors (e.g. composition). Drug elimination occurs through metabolic and excretory pathways that can also vary with body composition. The current data are limited to select drugs that have been reported in small studies or case reports. In the meantime, a rational approach to evaluate the potential influences of malnutrition and obesity can be used clinically based on available information. Antimicrobials are discussed as a useful example of this approach. Further advancement in this field would require collaboration between experts in body composition and those in drug disposition. Until more data are available, routine monitoring by the clinician of the protein–energy malnourished or obese patient receiving weight-based drug regimens is necessary.