This review discusses the current and future opportunities in the systemic treatment of hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer, with major risk factors including liver cirrhosis, hepatitis B and C, and non-alcoholic fatty liver disease. Systemic treatment is reserved for patients with advanced stages B and C who do not benefit from regional therapies. Over the past 15 years, the treatment landscape has evolved significantly, with the introduction of targeted therapies and immunotherapies. Sorafenib, a multi-target tyrosine kinase inhibitor, was the first approved systemic treatment for advanced HCC and showed improved survival compared to placebo. However, resistance and limited efficacy in some patients have led to the exploration of combination therapies and novel agents. Regorafenib, cabozantinib, lenvatinib, and other tyrosine kinase inhibitors have been evaluated as second-line treatments, with some showing improved outcomes compared to sorafenib. Immunotherapy, particularly PD-1/PD-L1 inhibitors like nivolumab and pembrolizumab, has also shown promise in HCC, with some studies demonstrating improved survival and response rates. Combination therapies, such as regorafenib with immunotherapy and lenvatinib with PD-1 inhibitors, have shown potential in improving clinical outcomes. Additionally, the combination of bevacizumab with atezolizumab has demonstrated significant improvements in OS and PFS in first-line treatment. The review highlights the importance of biomarkers in predicting response to treatment and the need for further research to optimize therapeutic strategies. Despite the progress, challenges remain, including resistance mechanisms, toxicity, and the need for more effective treatments. The future of HCC treatment may involve further combinations of targeted and immunotherapies, as well as the development of novel agents. The review concludes that while significant advancements have been made, ongoing research is essential to improve outcomes for patients with advanced HCC.This review discusses the current and future opportunities in the systemic treatment of hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer, with major risk factors including liver cirrhosis, hepatitis B and C, and non-alcoholic fatty liver disease. Systemic treatment is reserved for patients with advanced stages B and C who do not benefit from regional therapies. Over the past 15 years, the treatment landscape has evolved significantly, with the introduction of targeted therapies and immunotherapies. Sorafenib, a multi-target tyrosine kinase inhibitor, was the first approved systemic treatment for advanced HCC and showed improved survival compared to placebo. However, resistance and limited efficacy in some patients have led to the exploration of combination therapies and novel agents. Regorafenib, cabozantinib, lenvatinib, and other tyrosine kinase inhibitors have been evaluated as second-line treatments, with some showing improved outcomes compared to sorafenib. Immunotherapy, particularly PD-1/PD-L1 inhibitors like nivolumab and pembrolizumab, has also shown promise in HCC, with some studies demonstrating improved survival and response rates. Combination therapies, such as regorafenib with immunotherapy and lenvatinib with PD-1 inhibitors, have shown potential in improving clinical outcomes. Additionally, the combination of bevacizumab with atezolizumab has demonstrated significant improvements in OS and PFS in first-line treatment. The review highlights the importance of biomarkers in predicting response to treatment and the need for further research to optimize therapeutic strategies. Despite the progress, challenges remain, including resistance mechanisms, toxicity, and the need for more effective treatments. The future of HCC treatment may involve further combinations of targeted and immunotherapies, as well as the development of novel agents. The review concludes that while significant advancements have been made, ongoing research is essential to improve outcomes for patients with advanced HCC.