Simple SummaryThe liver is the world’s sixth most common primary tumor site, accountable for nearly 5% of all cancers and over 8% of cancer-related deaths. Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, accounting for about 75% of all primary liver tumors. One of the major therapeutic tools for this disease is liver transplantation. This therapeutic modality, as with the others, faces the obstacle of tumor recurrence, in addition to graft rejection. In this context, cell-free DNA is presented as a new tool for decision-making. In this article, we summarize the main aspects of this new tool, exploring its strengths and weaknesses in the treatment of HCC.AbstractThe liver is the world’s sixth most common primary tumor site, responsible for approximately 5% of all cancers and over 8% of cancer-related deaths. Hepatocellular carcinoma (HCC) is the predominant type of liver cancer, accounting for approximately 75% of all primary liver tumors. A major therapeutic tool for this disease is liver transplantation. Two of the most significant issues in treating HCC are tumor recurrence and graft rejection. Currently, the detection and monitoring of HCC recurrence and graft rejection mainly consist of imaging methods, tissue biopsies, and alpha-fetoprotein (AFP) follow-up. However, they have limited accuracy and precision. One of the many possible components of cfDNA is circulating tumor DNA (ctDNA), which is cfDNA derived from tumor cells. Another important component in transplantation is donor-derived cfDNA (dd-cfDNA), derived from donor tissue. All the components of cfDNA can be analyzed in blood samples as liquid biopsies. These can play a role in determining prognosis, tumor recurrence, and graft rejection, assisting in an overall manner in clinical decision-making in the treatment of HCC.