Background: Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is the fifth most common cancer in men and seventh among women worldwide. With increasing incidence worldwide, HCC is the second leading cause of cancer-related death. Chemoresistance and HCC recurrence after therapy complicate the treatment and result in poor survival. The challenges in treating advanced HCC despite the advanced therapies for HCC including immunotherapy involving adoptive T cell transfer therapy (cytokine-induced killer cells, tumor-infiltrating lymphocytes), checkpoint inhibitor therapy, oncolytic viral vaccines, and T cell receptor gene engineered T cell therapy; improved and better therapeutic modalities are needed. Chimeric antigen receptor (CAR)-T cell therapy showing promising clinical outcomes in hematological malignancies has also shown positive results in in vitro, xenografts, and some Phase I clinical trials for HCC. Thus, CAR-T cell therapy may have therapeutic efficacy in treating advanced HCC. This chapter focuses on discussing the therapeutic role of CAR-T cell therapy in the treatment of advanced HCC. Methods: A literature search following PRISMA guidelines was done, and articles describing CAR-T cell therapy in HCC were sorted out using PubMed, Google Scholar, and Embase. Hepatocellular carcinoma, immunotherapy, and CAR-T cell therapy search terms were used, and articles in the English language were included for this review. A total of 170 articles were sorted out and reviewed. Review articles more than 5 years old were removed and some articles describing T cell receptor (TCR) therapy were removed, and 75 articles were used with a focus on including original articles. Results: The literature search suggests that the systemic treatment of advanced HCC is cumbersome and multidisciplinary comprehensive treatment strategies with targeted therapies should be designed. Conclusion: CAR-T cell therapy hold promise in the treatment of advanced hepatocellular carcinoma, but larger clinical trials and improvement of CAR-T cells are needed for better safety and efficacy.