Muscle atrophy caused by unloading stress is a challenging problem for bed-rested patients or astronauts. However, countermeasures against these muscle atrophy have not been developed yet. Under unloading conditions, skeletal muscle mass is rapidly lost by the increase in protein breakdown and the decrease in protein synthesis. It has been shown that this enhancement of proteolysis in atrophying muscles results mainly from activation of the ubiquitin-proteasome proteolytic pathway. Previous our studies revealed that unloading stress led to skeletal muscle atrophy through the induction of ubiquitin ligase, Cbl-b (Casitas B-lineage lymphoma b) expression. Thus, Cbl-b inhibiters may be potent therapeutic and preventive sources against skeletal muscle atrophy caused by unloading stress.