Hepatocellular carcinoma is one of the most deadly liver malignancies found worldwide, with hepatitis virus infection being the prominent risk factor for this lesion. Patients with hepatocellular carcinoma are usually first diagnosed when in the advanced stage; thus, long-term clinical outcomes are poor and patients have limited treatment options. Currently, surveillance of hepatocellular carcinoma relies upon serological testing of alpha-fetoprotein levels and hepatic ultrasonography, which have low sensitivity and specificity, and are sometimes operator-dependent, respectively. Therefore, discovery of new biomarkers for early and accurate detection of hepatocellular carcinoma would be of great clinical value. Genomic and proteomic approaches are two major laboratory platforms for the identification of candidate hepatocellular carcinoma biomarkers based on profiling and validating with tumor and nontumor clinical samples. Frequently, these diagnostic markers have been found in association with genetic aberrations, protein-level alterations, post-translational modifications and immune functions. With the discovery of these biomarkers, earlier detection of hepatocellular carcinoma in high-risk subjects (e.g., cirrhosis and hepatitis carriers) becomes possible, which will enable clinicians to offer patients better clinical management and more effective treatment modalities.