Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease as major risk factors. Systemic treatment is reserved for patients in stages B and C who do not benefit from regional treatments. Over the past 15 years, the landscape of available therapeutics has expanded significantly, improving treatment outcomes. However, not all patients respond to these agents, and novel combinations and drugs are needed. This review summarizes the trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. It also discusses current evidence on resistance mechanisms and potential new targets in advanced HCC treatment. Key targeted therapies include receptor tyrosine kinases (RTKs) inhibitors, such as sorafenib, regorafenib, cabozantinib, lenvatinib, anlotinib, axitinib, donafenib, and apatinib. Immunotherapies, including PD-1/PD-L1 inhibitors and chimeric antigen receptor (CAR) T cells, have also shown promising results. The combination of targeted agents with immunotherapy has demonstrated clinical benefits, particularly in second-line treatment. The approval of sorafenib marked a breakthrough in HCC treatment, leading to subsequent trials and improved clinical outcomes. Recent trials have shown significant improvements in median overall survival (OS) and progression-free survival (PFS), with anti-angiogenic therapeutics combined with immunotherapy showing particular efficacy. Despite these advancements, challenges remain, including the development of resistance mechanisms, and new antiangiogenic agents are needed.Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease as major risk factors. Systemic treatment is reserved for patients in stages B and C who do not benefit from regional treatments. Over the past 15 years, the landscape of available therapeutics has expanded significantly, improving treatment outcomes. However, not all patients respond to these agents, and novel combinations and drugs are needed. This review summarizes the trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. It also discusses current evidence on resistance mechanisms and potential new targets in advanced HCC treatment. Key targeted therapies include receptor tyrosine kinases (RTKs) inhibitors, such as sorafenib, regorafenib, cabozantinib, lenvatinib, anlotinib, axitinib, donafenib, and apatinib. Immunotherapies, including PD-1/PD-L1 inhibitors and chimeric antigen receptor (CAR) T cells, have also shown promising results. The combination of targeted agents with immunotherapy has demonstrated clinical benefits, particularly in second-line treatment. The approval of sorafenib marked a breakthrough in HCC treatment, leading to subsequent trials and improved clinical outcomes. Recent trials have shown significant improvements in median overall survival (OS) and progression-free survival (PFS), with anti-angiogenic therapeutics combined with immunotherapy showing particular efficacy. Despite these advancements, challenges remain, including the development of resistance mechanisms, and new antiangiogenic agents are needed.