Hepatocellular carcinoma （HCC） is one of the leading causes of cancer-related mortality worldwide and is also one of the most common malignant tumors in clinical practice in our country. HCC is characterized by insidious onset and rapid progression， and most patients are in the advanced stage at the time of diagnosis， resulting in a poor prognosis. Alpha-fetoprotein （AFP）-negative hepatocellular carcinoma （ANHCC） accounts for approximately 30% — 40% of all HCC cases， and the traditional diagnostic biomarker， serum AFP， has insufficient sensitivity in this population， which can easily lead to missed diagnoses. This article reviews the potential of classic biomarkers， novel protein markers， liquid biopsy markers， and metabolomics markers in the early screening for ANHCC， in order to improve the early diagnosis rate of ANHCC and reduce the disease burden of liver cancer.