Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC.