Deubiquitinating enzymes (DUBs) play an important role in the regulation of cellular homeostasis, cell proliferation, division as well as apoptosis, etc. Ubiquitin C-terminal hydrolases L3 (UCH-L3), a kind of cysteine protease, is a member of the DUBs family. It catalyzes and releases those attached intact ubiquitin molecules from peptides chain of target proteins to regulate the degradation rate of target protein and recycle the ubiquitin molecules. The study on this hydrolases is inadequate up to now. Many DUBs have been shown to participate in a variety of carcinoma progression. High expressions of DUBs in some kinds of disease and tumor indicate their potential role. In this review, we will discuss about the Ubiquitin C-terminal hydrolases L3 and its potential role in disease and cancer.