Guided liver biopsy is commonly employed to determine the identity of distinct hepatic nodules detected on imaging studies of patients with advanced stage chronic liver diseases. Discrimination among large regenerative nodule, dysplastic nodule and well-differentiated hepatocellular carcinoma is often difficult and relies on subtle histologic findings. Sampling is an important consideration in biopsy material, as compared to resection specimens, because the diagnostic features may be focal within the nodule. Immunohistochemical stains may be useful in distinguishing between large regenerative and dysplastic nodule on the one hand, versus early and classic hepatocellular carcinoma on the other. Ongoing research on the early lesions of hepatocarcinogenesis is enhancing our understanding of the sequential steps of this process and provides novel tools for histopathologic differential diagnosis.