Abstract: Ubiquitin-like proteins are structurally similar to ubiquitin. These proteins are processed, activated, conjugated, and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. Ubiquitin-like proteins regulate a wide array of cellular processes through modification processes, such as nuclear-cytosolic transport, transcriptional regulation, protein stability, response to stress, and progression through the cell cycle. A large number of recent studies have found dysfunctional ubiquitin-like proteins in hepatocellular carcinoma. These proteins are important in tumorigenesis, cell proliferation, apoptosis, and angiogenesis. Anticancer drug studies revealed that regulating protein modification by using ubiquitin-like proteins may alter the anti-tumor effects of chemotherapy and thus influence the chemosensitivity of hepatocellular carcinoma. Results indicate that ubiquitin-like proteins may become a new target for cancer therapy. The mechanism of ubiquitin-like proteins in tumorigenesis and hepatocellular carcinoma progression is of great significance in the diagnosis and treatment of hepatocellular carcinoma.