The prognosis for hepatocellular carcinoma (HCC) is poor and has not improved in recent years, largely owing to lack of early diagnosis, frequent recurrence after surgery and resistance to chemotherapy. Proteomics holds the promise of improving our understanding of HCC carcinogenesis and progression as well as of discovering novel diagnostics and therapeutics. Proteomic analyses of HCC cell lines, animal models and serum and tumor tissue from patients with HCC have been performed to date. Proteomic technologies have greatly improved in the past few years as reviewed here. It is anticipated that with the recent development of protein tagging, protein separation methods and mass spectrometry sensitivity, proteomic studies of HCC will allow the identification of diagnostic and prognostic biomarkers as well as therapeutic targets, which could greatly improve the clinical management of HCC patients.