The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene amplification of selected oncogenes. The changes observed in different HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation. An understanding of the molecular pathogenesis of HCC may provide new markers for tumor staging, for assessment of the relative risk of tumor formation, and open new opportunities for therapeutic intervention.