Negative N balance, and skeletal muscle wasting are associated with many disease states. Depletion of skeletal muscle mass is recognized as critical to overall survival of the patient and can prolong rehabilitation to normal physiological function following recovery. The biochemical mechanisms of muscle wasting have been most fully investigated in animal models. These studies indicate a role for suppressed protein synthesis as well as activated proteolysis, and therefore to a need for both anabolic as well as anti-catabolic therapies. Multiple humoral factors are implicated in altered muscle protein metabolism, however the identity of all of the factors involved and their interrelationships are less well characterized. The role of specific mediators in different clinical instances of muscle protein loss is relatively poorly understood, and successful treatment will depend on the ability to identify the different catabolic phenotypes in patients.