Plasma membrane disruptions have been documented under physiological conditions in lots of mechanically active tissues, such as in skeletal muscle, the stratified epithelium that covers our body, the endothelia that line our blood vessels, the epithelial barrier of our gastrointestinal tract. Timely and effective plasma membrane repair (PMR) mechanisms have evolved to rapidly reseal a membrane breach to ensure cell survival. Otherwise, these membrane disruption events initiate a “death cascade”. PMR is coordinated by many “tinkerers”, which have a clear division of labor and show certain timing characteristics. The endosomal sorting complexes required for transport (ESCRT) is the “tinkerer” found recently who plays a key role in the repair of plasma membrane disruptions. It is composed of ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III, VPS4-VTA1 and ALIX, which take part in the budding and the formation of multivesicular body (MVB). This paper reviews two repair methods mediated by ESCRT system with budding and the formation of MVB. The function of ESCRT complex in plasma membrane repair can improve membrane disruptions, which is able to be used as an effective prevention and treatment strategy for cancer, Alzheimer’s disease, muscle injury and muscular dystrophy.