Glypican-3 (GPC3) is highly expressed in human hepatocellular carcinoma (HCC) and a growing body of evidence supports the role of GPC3 in HCC pathogenesis. In this review, we discuss recent developments regarding the regulation of GPC3 in HCC and provide insight about GPC3 as a potential therapeutic target in liver cancer. One of the most well studied pathways related to the biological functions of GPC3 is the Wnt signaling pathway. GPC3 may form a complex with Wnt and stimulates HCC growth. GPC3 does this by facilitating and/or stabilizing the interaction between Wnt and Frizzled, leading to the activation of downstream signaling pathways. This signaling complex is also affected by Sulfatase 2 (SULF2), a heparin-degrading endosulfatase. Removing the sulfate groups from GPC3 enhances Wnt signaling and HCC proliferation suggesting that GPC3, Wnts and SULF2 may be part of "a glypican-Wnt/growth factor complex", which may determine cell growth, differentiation and migration. Given the high expression of GPC3 in HCC, GPC3 has been suggested as a potential target for antibody-based therapy for liver cancer. A monoclonal antibody (GC33) is being evaluated in clinical studies as a single agent or in combination with Sorafenib to treat patients with advanced or metastatic HCC. Ongoing clinical trials will help define the utility of GPC3 as a novel target for liver cancer therapy.