The underlying molecular basis for the heterogeneity in human liver cancer, hepatocellular carcinoma (HCC), is largely unknown. As with most other human cancers, the heterogeneous nature of HCC has hampered both treatment and prognostic predictions. Global gene expression profiling of human cancers is a promising new technology for refining the diagnosis and prognosis of HCC as well as for identifying potential therapeutic targets. Improved molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, improve the selection of treatments for specific molecular subtypes of HCC, and ultimately improve the clinical outcome of HCC patients. We review the recent advances in gene expression profiling of HCC and discuss the biological and clinical insights obtained from these studies.