Amphiregulin (AR) is a member of the epidermal growth factor family and a ligand of the epidermal growth factor receptor (EGFR). As other ligands of the EGFR, AR is synthesized as a precursor that is shed from the plasma membrane by metalloproteases. Hyperactive autocrine loops involving AR production have been described in a variety of tumors, and this growth factor is thought to play a non-redundant role in cancer development. AR expression is not detected in the normal liver, however it is readily induced during acute liver injury and behaves as a potent pro-regenerative and survival factor. Increased AR expression is also detected in human chronic liver injury (liver cirrhosis), which is considered a pre-neoplastic condition. Recent evidences suggest that AR can play a unique role in liver tumorigenesis and in the maintenance of the neoplastic phenotype of hepatocarcinoma cells. In this review, we summarize some aspects of AR patho-biology and the rationale behind its definition as a novel target in hepatocarcinoma therapy.