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Introduction While sorafenib dominated the therapeutic arena in advanced hepatocellular carcinoma (HCC) for almost a decade, newer agents and combinations have been changing the therapeutic landscape in the last years.Areas covered The authors outline the etiopathogenesis and evaluate the diagnostics in HCC, followed by a comprehensive review of the currently approved and experimental treatment approaches, with a focus on various systemic agents and combinations of agents. The manuscript was subdivided into relevant categories, thus maki