Introduction The most common biomarker for HCC is serum alpha-fetoprotein (AFP). AFP is used for screening and diagnosing HCC, and also, it is used for predicting prognosis and monitoring the response to treatment. Discussion AFP secretion is associated with poor tumor histologic grade and aggressive tumor biological behavior. The risk of dropout on the waiting list for liver transplantation and the risk of tumor recurrence after liver transplantation are associated with high AFP serum levels. Therefore, using AFP levels for selecting patients to include on the liver transplantation waiting lists is critical. It is also known that a low AFP serum level before liver transplantation has limited informative value, but high AFP levels prior to liver transplantation indicate a higher risk for HCC recurrence. Conclusion AFP's performance as a screening, diagnostic, and prognostic marker for HCC is not ideal, but it is the most frequently used biomarker in the management of HCC.