Hepatocellular carcinoma (HCC) is a major global health issue, with over 700,000 new cases diagnosed annually. It is the leading cause of cancer-related death in patients with cirrhosis and is associated with viral hepatitis, alcohol-related liver disease, and non-alcoholic steatohepatitis. The molecular pathogenesis of HCC is complex and heterogeneous, and current molecular information has not significantly influenced treatment decisions. Regular surveillance imaging is widely practiced in cirrhotic patients, especially for early-stage HCC, which can be effectively treated. The approach to resection versus transplantation varies globally due to resource availability, expertise, and donor availability. The Milan Criteria remain the standard for transplantation, with some expanded criteria proposed. For intermediate-stage HCC, options include radiofrequency ablation, transarterial chemoembolisation, and radioembolisation. For advanced HCC, sorafenib remains the best-supported systemic therapy. While many trials have failed to improve established therapies, further studies on sequential or combined treatments are needed. New concepts for patient selection and stratification in second-line studies are also discussed. HCC is a major health problem worldwide, with over 700,000 new cases diagnosed annually. Major risk factors include hepatitis B or C viruses, alcohol-related cirrhosis, and non-alcoholic steatohepatitis. Smoking increases the risk, while coffee may reduce it. The mortality rate in most countries equals the incidence rate, indicating a lack of effective therapies at diagnosis. In Japan, where HCC surveillance is aggressive, the incidence rate exceeds the mortality rate. Over 90% of HCC cases develop in chronic liver disease, primarily cirrhosis. Preventing HCC involves avoiding risk factors for chronic liver disease. Vaccination and antiviral treatment can help, but delayed antiviral intervention reduces effectiveness. Long-term interferon treatment does not reduce HCC risk, and agents like metformin, propranolol, and retinoids require further study. This review examines current understanding and future challenges in three areas: molecular events driving tumour development, outcome prediction, and available treatments. Molecular classification of HCC has revealed significant genetic heterogeneity, with differences between patients, tumour nodules, and even within a single nodule. Genetic analysis includes various techniques, such as genome-wide association studies, mRNA expression profiling, miRNA profiling, and copy number aberrations. However, interpreting genetic data is challenging due to the distinction between driver and passenger mutations. The genetic profile of HCC may vary based on the underlying liver disease and patient genetics. HCC is the main cause of death in cirrhotic patients, and regular ultrasound screening is recommended for at-risk patients. The Barcelona Clinic Liver Cancer (BCLC) staging system is recommended for outcome prediction, treatment planning, and research. Technical feasibility is not a surrogate for improved survival, and therapeutic recommendationsHepatocellular carcinoma (HCC) is a major global health issue, with over 700,000 new cases diagnosed annually. It is the leading cause of cancer-related death in patients with cirrhosis and is associated with viral hepatitis, alcohol-related liver disease, and non-alcoholic steatohepatitis. The molecular pathogenesis of HCC is complex and heterogeneous, and current molecular information has not significantly influenced treatment decisions. Regular surveillance imaging is widely practiced in cirrhotic patients, especially for early-stage HCC, which can be effectively treated. The approach to resection versus transplantation varies globally due to resource availability, expertise, and donor availability. The Milan Criteria remain the standard for transplantation, with some expanded criteria proposed. For intermediate-stage HCC, options include radiofrequency ablation, transarterial chemoembolisation, and radioembolisation. For advanced HCC, sorafenib remains the best-supported systemic therapy. While many trials have failed to improve established therapies, further studies on sequential or combined treatments are needed. New concepts for patient selection and stratification in second-line studies are also discussed. HCC is a major health problem worldwide, with over 700,000 new cases diagnosed annually. Major risk factors include hepatitis B or C viruses, alcohol-related cirrhosis, and non-alcoholic steatohepatitis. Smoking increases the risk, while coffee may reduce it. The mortality rate in most countries equals the incidence rate, indicating a lack of effective therapies at diagnosis. In Japan, where HCC surveillance is aggressive, the incidence rate exceeds the mortality rate. Over 90% of HCC cases develop in chronic liver disease, primarily cirrhosis. Preventing HCC involves avoiding risk factors for chronic liver disease. Vaccination and antiviral treatment can help, but delayed antiviral intervention reduces effectiveness. Long-term interferon treatment does not reduce HCC risk, and agents like metformin, propranolol, and retinoids require further study. This review examines current understanding and future challenges in three areas: molecular events driving tumour development, outcome prediction, and available treatments. Molecular classification of HCC has revealed significant genetic heterogeneity, with differences between patients, tumour nodules, and even within a single nodule. Genetic analysis includes various techniques, such as genome-wide association studies, mRNA expression profiling, miRNA profiling, and copy number aberrations. However, interpreting genetic data is challenging due to the distinction between driver and passenger mutations. The genetic profile of HCC may vary based on the underlying liver disease and patient genetics. HCC is the main cause of death in cirrhotic patients, and regular ultrasound screening is recommended for at-risk patients. The Barcelona Clinic Liver Cancer (BCLC) staging system is recommended for outcome prediction, treatment planning, and research. Technical feasibility is not a surrogate for improved survival, and therapeutic recommendations