There is considerable overlap in morphologic features in well-differentiated hepatocellular lesions necessitating the use of immunohistochemistry and other techniques for diagnosis. Map-like pattern with glutamine synthetase in focal nodular hyperplasia and cytoplasmic staining with serum amyloid associated protein in inflammatory hepatocellular adenoma (HA) are useful for this distinction. The distinction of well-differentiated hepatocellular carcinoma (HCC) and HA in noncirrhotic liver is facilitated by demonstrating glypican-3 and cytogenetic changes like gains of chromosomes 1 and 8. Nuclear staining with β-catenin and/or diffuse staining with glutamine synthetase strongly favors well-differentiated HCC or HA with high risk for HCC. In a cirrhotic liver, separation of early HCC from high-grade dysplastic nodule requires identification of stromal invasion, which can be highlighted by absence of keratin 7-positive ductular reaction. Combined use of heat shock protein 70, glutamine synthetase, and glypican-3 can be useful as positivity for 2 or more of these markers has shown high specificity for HCC in early studies.