Hepatocyte paraffin-1 (HepPar-1) is a recently developed monoclonal antibody that appears to identify an antigen unique to hepatocellular mitochondria. This article reviews the use of this new antibody in the differential diagnosis of primary hepatocellular neoplasms, cholangiocarcinomas, and carcinomas metastatic to the liver. Hepatocyte paraffin-1 appears to be the most sensitive and specific positive marker of hepatocellular differentiation, but like any immunohistochemical marker, should be interpreted only in the context of the overall clinicopathologic picture and as part of a panel of antibodies.