For a decade, sorafenib remained the only approved first-line treatment and standard of care for advanced hepatocellular carcinoma. The treatment landscape has been evolving rapidly over the past 2 years with the approval of additional first-and second-line systemic treatments, most of which are targeted therapies. The expected approval of immunotherapies constitutes a paradigm shift: for the first time in years, a checkpoint inhibitor in combination with a VEGF antibody recently outperformed sorafenib with regards to efficacy. The wider availability of systemic therapies increases the chance for longer overall survival but raises new questions concerning the role of local options, treatment choice and sequential treatment. Following an expert discussion at the German Cancer Congress 2020 in Berlin, this article aims to summarize the current evidence on and experience of treatment choice and sequence in first- and second-line therapy.