Advanced hepatocellular carcinoma (HCC) has a poor prognosis with limited treatment options. During the last decade, sorafenib, a multi-tyrosine kinase inhibitor (TKI), has been the only available systemic agent for first-line treatment of unresectable HCC (1). Recently, another multi-TKI, lenvatinib, was added to the list of first-line treatment alteatives based on the results of the phase III RREFLECT trial. For second-line treatment, two multi-TKIs, regorafenib and cabozantinib, were approved in 2016 and 2018, respectively. Among other targeted therapies, ramucirumab and an anti-PD-1 antibody, nivolumab, will soon be added in a second-line setting to the therapeutic armamentarium. These agents, however, generally lead to disease stabilization rather than tumor shrinkage. Achievement of complete remission with available systemic treatments still remains rare, however, and therapeutic breakthroughs are still needed.