Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of all cases. It is a global health challenge, with an estimated 1 million cases by 2025. The main risk factors for HCC include hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, although non-alcoholic steatohepatitis (NASH), associated with metabolic syndrome or diabetes, is becoming a more frequent risk factor in the West. NASH-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, but these are not yet translated into clinical practice. Diagnosis based on non-invasive criteria is challenged by the need for molecular information that requires tissue or liquid biopsies. Current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials, and three additional therapies have obtained accelerated FDA approval. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages. HCC is the leading cause of death in patients with cirrhosis, with an annual incidence of 1–6%. The major risk factors for HCC include chronic alcohol consumption, diabetes or obesity-related NASH, and infection by HBV or HCV. Other less prevalent risk factors include cirrhosis from primary biliary cholangitis, haemochromatosis, and α1-antitrypsin deficiency. The molecular pathogenesis of HCC varies according to the distinct genotoxic insults and aetiologies. Although our understanding of the pathophysiology and drivers of the disease has improved, this knowledge is yet to be translated into clinical practice. Approximately 25% of HCC tumours present actionable mutations; however, the prevalence of most mutations is <10%, thereby complicating proof-of-concept studies. Dominant mutational drivers in HCC, such as TERT, TP53 and CTNNB1, remain undruggable. In addition, the translation of molecular and immune classes into biomarkers that guide therapies is still under investigation. The diagnosis of HCC is usually based on non-invasive criteria, although there is a growing need for molecular characterization of the tumour using tissue biopsies in clinical practice. In terms of prevention, beyond vaccines preventing HBV infection and anti-viral therapies for HBV and HCV infection, cumulative data support the preventive role of coffee and aspirin. The management of HCC has markedly improved since the early 2010s. Hepatic resection and liver transplantation have been the mainstay curative treatments in HCC cases. Refinements in patient selection have resulted in enhanced surgical resection outcomes and remarkable 10Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of all cases. It is a global health challenge, with an estimated 1 million cases by 2025. The main risk factors for HCC include hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, although non-alcoholic steatohepatitis (NASH), associated with metabolic syndrome or diabetes, is becoming a more frequent risk factor in the West. NASH-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, but these are not yet translated into clinical practice. Diagnosis based on non-invasive criteria is challenged by the need for molecular information that requires tissue or liquid biopsies. Current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials, and three additional therapies have obtained accelerated FDA approval. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages. HCC is the leading cause of death in patients with cirrhosis, with an annual incidence of 1–6%. The major risk factors for HCC include chronic alcohol consumption, diabetes or obesity-related NASH, and infection by HBV or HCV. Other less prevalent risk factors include cirrhosis from primary biliary cholangitis, haemochromatosis, and α1-antitrypsin deficiency. The molecular pathogenesis of HCC varies according to the distinct genotoxic insults and aetiologies. Although our understanding of the pathophysiology and drivers of the disease has improved, this knowledge is yet to be translated into clinical practice. Approximately 25% of HCC tumours present actionable mutations; however, the prevalence of most mutations is <10%, thereby complicating proof-of-concept studies. Dominant mutational drivers in HCC, such as TERT, TP53 and CTNNB1, remain undruggable. In addition, the translation of molecular and immune classes into biomarkers that guide therapies is still under investigation. The diagnosis of HCC is usually based on non-invasive criteria, although there is a growing need for molecular characterization of the tumour using tissue biopsies in clinical practice. In terms of prevention, beyond vaccines preventing HBV infection and anti-viral therapies for HBV and HCV infection, cumulative data support the preventive role of coffee and aspirin. The management of HCC has markedly improved since the early 2010s. Hepatic resection and liver transplantation have been the mainstay curative treatments in HCC cases. Refinements in patient selection have resulted in enhanced surgical resection outcomes and remarkable 10