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Hepatocellular carcinoma (HCC) has distinct morphologic features and can be identified in the majority of cases by routine hematoxylin and eosin (H&E)-stained formalin-fixed paraffin-embedded sections. However, distinguishing a well-differentiated HCC from normal or regenerative tissue may be very difficult in some cases, particularly in small needle aspiration or core biopsies. Furthermore, some of the unusual morphologic variants, including clear-cell, pleomorphic, and sarcomatoid variants, may be mistaken for metastases. Similarly, metastases from various primary tumors to the liver may be mistaken for primary hepatic tumors. In this overview, we summarize the immunohistochemical and molecular markers that have been developed to address these diagnostic challenges. Among the numerous diagnostic markers studied, pCEA, HepPar 1, CD34, CK 7, CK 19, CK 20, and albumin in situ (ISH) have been found to be valuable in distinguishing HCC from metastatic neoplasms of extrahepatic sites.