Hepatocellular carcinoma (HCC) remains a major cause of mortality in patients with chronic liver disease worldwide. Early detection of HCC is critical to providing effective treatment and can have a significant impact on survival. In addition, effective surveillance following hepatic resection or locoregional ablative therapy can identify early recurrence and optimize long-term outcomes. Currently available serum tumor markers, including alpha-fetoprotein (AFP), are characterized by low sensitivity in the detection of HCC. Advances in genomic, proteomic, metabolomic, and glycomic profiling may provide a means to identify unique molecular signatures and characterization of complex processes associated with HCC incidence and recurrence. The development of highly sensitive and specific serum biomarkers for HCC may greatly enhance early detection rates, risk assessment in treatment candidates, and identification of potential new targets for anticancer therapy.