BackgroundMost patients with hepatocellular carcinoma (HCC) are diagnosed in advanced stages where treatment with curative intent is no longer possible. Because of the low efficacy of cytotoxic chemotherapies in HCC, effective systemic therapies were not available for many years. In 2008, the approval of the tyrosine kinase inhibitor (TKI) sorafenib ended this era. Since then, several further substances such as TKIs, anti-VEGF antibodies and immunotherapeutics have proven their efficacy in the treatment of advanced HCC. Here the advent of immune checkpoint inhibitors (CPIs) in particular represented a major advance in systemic therapy for HCC.ObjectivesIn this work, we provide an overview of the development of systemic therapy for HCC.Materials and methodsRelevant articles were identified in public databases. Clinical trial information was obtained from the Clinicaltrials.gov trial registry. Reported drug approvals were obtained from publicly available information of the European Medicines Agency and the U.S. Food and Drug Administration.ConclusionsCPI-based combination therapies have revolutionized the treatment of HCC. In clinical trials, which led to approval, good efficacy was observed in the form of significantly higher objective antitumoral responses compared to sorafenib, which translated to long-term survival that had not been previously attained. Current clinical trials are investigating the use of CPI with transarterial chemoembolization or other local therapies for earlier tumor stages, as well as new CPI-based combination therapies. These efforts may help to further improve the prognosis of patients with HCC. Inclusion of HCC patients in these clinical trials is therefore highly recommended.