Increased proteolysis contributes to the muscle wasting seen in several pathological conditions (e.g. cancer, sepsis, diabetes, burn injury, trauma, etc) and during fasting. Enhanced proteolysis in skeletal muscle, the major protein reservoir in the body, is a key metabolic adaptation providing the organism with free amino acids for energy production via gluconeogenesis and direct oxidation. Net mobilisation of muscle protein in pathological situations also provides free amino acids for acute phase protein synthesis in the liver, and for protein synthesis in vital organs (e.g. brain and heart). However, sustained muscle wasting rapidly results in increased morbidity and mortality. The lysosomal, Ca2+-activated and ubiquitin-proteasome-dependent pathways and the caspases are the most important processes responsible for the breakdown of the bulk of skeletal muscle protein. The activation of the ubiquitin-proteasome system (UPS) is mainly responsible for the muscle wasting that occurs in various animal models of cachexia. This activation involves alterations in the ubiquitination, deubiquitination and proteolytic machineries (1). Other proteolytic enzymes act upstream (possibly caspase-3, m-calpain, and/or cathepsin L) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids (1). Recent studies have identified a few critical proteins that seem necessary for muscle wasting (i.e. the muscle-specific MuRF-1 and MAFbx/atrogin-1 ubiquitin-protein ligases E3s)(2). The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting (3). I discuss the nature of the substrates of the UPS, and the evidence that the UPS is activated in weight-losing patients.