Hepatocellular carcinoma (HCC) is a severe condition that is found worldwide. The current methods of HCC screening and diagnosis depend mainly on tumor imaging techniques. Using tumor biomarkers to detect cancer has helped to screen for disease and avoid wasting medical resources. Serum α-fetoprotein (AFP), a glycoform of AFP that reacts with Lens culinaris agglutinin (AFP-L3), and des-gamma carboxyprothrombin (DCP) are biomarkers commonly used to detect HCC in medical practice around the world. However, each of these biomarkers is imperfect when used alone and each has limitations in terms of the sensitivity and specificity with which it detects HCC. Presumably, a combination of these biomarkers is a practical way to improve their performance. That said, novel biomarkers of HCC are being sought to diagnose the disease and also to optimize the treatment modality, to predict prognosis or recurrence, and to discover novel targets for therapeutic interventions.