Abstract: Glypican-3 belongs to the glypican family, and it has been identified as diagnostic molecule in hepatocellular carcinoma (HCC) due to its high expression in HCC cells and patients' serum. Additionally, data indicate that it plays an important role in the initiation and progression of HCC. Nowadays, GPC-3-targeted therapies, including antibodies, peptide vaccines, and genetic therapies (miRNA, shRNA, and siRNA) can inhibit tumor growth. In this review, we will summarize the molecular structure of GPC-3, and its role in pathogenesis, diagnosis, and targeted therapies in HCC and make further exploration of clinical implications of GPC-3 in HCC.