Cachexia represents the clinical consequence of a chronic, systemic inflammatory response, and its manifestations differ considerably from those of starvation. Although cachexia is classically associated with chronic infections and malignant conditions, some of its elements have been identified in a wide variety of chronic diseases and in aging persons. Cachexia has repeatedly been associated with adverse clinical outcomes. The changes seen in cachexia are multidimensional and highly coordinated. Most obvious is a redistribution of the body's protein content, with preferential depletion of skeletal muscle and an increase in the synthesis of proteins involved in the response to tissue injury-the so-called acute-phase response. The physiologic, metabolic, and behavioral changes of cachexia are tightly regulated by cytokines, which signal the synthesis of acute-phase proteins as well as changes in intermediary metabolism that provide substrate and energy. The metabolic adaptations, notably the increase in the rate of protein degradation, limit the ability of hypercaloric feeding to reverse the depletion of lean mass. Recent studies have demonstrated the ability of anabolic and anticatabolic agents to mitigate the loss of skeletal muscle and to improve clinical outcomes in selected circumstances. Preclinical initiatives target the cytokine regulation of protein metabolism. It should be stressed that metabolic manipulation in cachexia could have positive or negative clinical effects, which must be distinguished through appropriate clinical trials.