<p>Ubiquitin-specific proteases (USPs) are a large family of deubiquitinating enzymes that all serve the important function of removing ubiquitin moieties from target proteins, thereby maintaining cellular homeostasis. Post-translational modifications, including ubiquitin modifications, play a crucial role in regulating protein stability, localization, and function, thereby profoundly influencing cellular processes such as cell cycle progression, signal transduction, and the response to DNA damage. Increasingly extensive evidence indicates that altered USP activity creates dysfunction of these fundamental cellular pathways and initiates and promotes multiple cancers, including hepatocellular carcinoma (HCC). In HCC, aberrant USP activity directly alters tumor cell proliferation and survival pathways, as well as metastasis, by manipulating oncogenic signaling networks and cellular stress responses. The altered expression or function of multiple USPs has been associated with aggressiveness and poor clinical outcomes, suggesting that USPs may have potential as prognostic biomarkers. Additionally, USPs are ideal therapeutic targets because their enzymatic activity can be selectively inhibited, thereby restoring normal ubiquitination-dependent signaling pathways that are frequently hijacked in cancer. The goal of this review is to provide an overview of current knowledge on the roles of USPs in HCC pathogenesis, with an emphasis on our understanding of their combined effect on major biological processes that underpin or augment tumor development. We highlight our understanding of how USPs regulate oncogenic pathways and cellular behavior in HCC, which forms the basis for this important area of future research aimed at developing novel USP-based therapies. Understanding USP biology in HCC represents a significant opportunity to inform the development of new cancer therapies.</p>