Ubiquitinating enzymes (UBEs) catalyze protein ubiquitination, a reversible process countered by deubiquitinating enzyme (DUB) action. Five DUB subfamilies are recognized, including the USP, UCH, OTU, MJD, and JAMM enzymes. The deubiquitinating enzyme ubiquitin-specific protease 8 (USP8/UBPy) is a cysteine protease belonging to the USP/UBP subfamily. Research studies have shown that USP8 is an essential growth-regulated enzyme indispensible for cell proliferation and survival. Indeed, conditional knock-out of murine USP8 was shown to promote a dramatic loss in expression of receptor tyrosine kinases, including EGFR, ErbB3, and c-Met. In agreement with these findings, USP8 inactivation leads to enhanced ubiquitination of ligand-activated EGFR. Furthermore, phosphorylation of USP8 at Ser680 results in its binding of 14-3-3, catalytic inactivation, and reduced EGFR deubiquitination. It appears as though USP8, in conjunction with components of the ESCRT-0 complex, plays an integral role in the early endosomal sorting machinery that functions to protect EGFR from lysosomal degradation.