Early specific diagnosis and effective treatment of hepatocellular carcinoma (HCC) are crucial. Expression of membrane-associated heparan sulfate proteoglycan glypican-3 (GPC-3) was recently found to increase as part of the malignant transformation of hepatocytes, and this increase is especially marked in patients with hepatitis B virus (HBV) infection, periportal cancerous embolus, or extra-hepatic metastasis. According to data from basic and clinical studies, the oncofetal antigen GPC-3 is a highly specific diagnostic biomarker of HCC and an indicator of its prognosis, and GPC-3 is also a promising target molecule for HCC gene therapy since it may play a crucial role in cell proliferation, metastasis, and invasion and it may mediate oncogenesis and oncogenic signaling pathways. This review summarizes recent advances in the use of oncofetal antigen GPC-3 to diagnose HBV-related HCC, estimate its prognosis, and its targeted therapy.