Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma reviews the current and emerging systemic treatments for advanced hepatocellular carcinoma (HCC). The article highlights that traditional chemotherapy is rarely used, with immunotherapy, tyrosine kinase inhibitors (TKIs), and VEGF inhibitors being the main options. Immune checkpoint inhibitors targeting various receptors are under clinical evaluation, and three-drug regimens may represent the future of HCC treatment. Other immune-modulatory approaches, including CAR T-cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines, are in early clinical trials. Targeted therapies remain limited but hold potential for growth. The article discusses the shift away from first-line sorafenib, emphasizing the need for better comparative treatments. It outlines the evolution of first-line treatments, including the approval of immunotherapy regimens like atezolizumab plus bevacizumab and tremelimumab plus durvalumab. Second-line and beyond treatments include regorafenib, cabozantinib, ramucirumab, and combinations of immunotherapy and TKIs. The article also explores future directions, including three-drug regimens and novel immune-modulatory approaches. It discusses challenges such as drug resistance, the role of biomarkers, and the need for more effective treatments. The review concludes that while immunotherapy and TKIs have shown promise, further research is needed to optimize treatment strategies for HCC.Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma reviews the current and emerging systemic treatments for advanced hepatocellular carcinoma (HCC). The article highlights that traditional chemotherapy is rarely used, with immunotherapy, tyrosine kinase inhibitors (TKIs), and VEGF inhibitors being the main options. Immune checkpoint inhibitors targeting various receptors are under clinical evaluation, and three-drug regimens may represent the future of HCC treatment. Other immune-modulatory approaches, including CAR T-cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines, are in early clinical trials. Targeted therapies remain limited but hold potential for growth. The article discusses the shift away from first-line sorafenib, emphasizing the need for better comparative treatments. It outlines the evolution of first-line treatments, including the approval of immunotherapy regimens like atezolizumab plus bevacizumab and tremelimumab plus durvalumab. Second-line and beyond treatments include regorafenib, cabozantinib, ramucirumab, and combinations of immunotherapy and TKIs. The article also explores future directions, including three-drug regimens and novel immune-modulatory approaches. It discusses challenges such as drug resistance, the role of biomarkers, and the need for more effective treatments. The review concludes that while immunotherapy and TKIs have shown promise, further research is needed to optimize treatment strategies for HCC.