Hepatocellular carcinoma (HCC) is a significant health challenge being the most common form of primary liver cancers worldwide. Worldwide, viral infections are the main risk factors for HCC development particularly in Asia and Africa; non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West (Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA. JAMA Oncol 3:1683, 2017). The diagnosis of HCC relies mainly on non-invasive radiologic criteria, alongside serum markers and biopsy in case of equivocal imaging. The treatment of HCC is dependent on the stage of diagnosis and the severity of underlying liver disease requiring the evaluation of a multidisciplinary team. Potential treatment strategies include surgical resection, liver transplantation, loco-regional treatment, radiation, and systemic therapy. This chapter aims to provide a comprehensive overview of the management of HCC. Topics of surgical resection and ablation have dedicated chapters elsewhere in this textbook.