Tumor susceptibility gene 101 protein (TSG101) is a multi-domain cytoplasmic protein and fundamental component of ESCRT complex I, which is intimately involved in regulating the trafficking of proteins throughout the endosomal compartment. In addition to regulating the sorting of ubiquitinated cargo proteins within the endosomal compartment, TSG101 is involved in regulating diverse biological processes, such as cell proliferation, viral budding and release, and exosome biosynthesis. While it is clear that TSG101 expression levels are tightly controlled and complete loss of expression causes embryonic lethality due to cell cycle arrest and cell death, the role of TSG101 in malignancy has yet to be fully elucidated. Indeed, TSG101 was initially dubbed a tumor suppressor but there are multiple studies that demonstrate an elevated expression in human cancers.