Hepatocellular carcinoma (HCC) is a highly malignant disease and early diagnosis rates remain to be unsatisfactory. Owing to this limitation, advances in treatment options including liver transplantation (LT) are limited to improve survival. Recent HCC guidelines no longer recommend alpha-fetoprotein (AFP) as a surveillance and diagnostic tool for HCC. Hence, utilization of novel biomarkers has become imperative to improve disease management strategies. Noninvasive, serum-based biomarkers are potential options to aid early diagnosis as well as prompting treatment. However, further studies are required to find out the accuracy and potential of these approaches and introduce into clinical practice.