|Sorafenib became the first approved systemic agent for hepatocellular carcinoma (HCC) in 2007 [Llovet JM et al: New Engl J Med 2008; Cheng AL et al: Lancet Oncol 2009]. The approval of sorafenib has stimulated a lot of efforts in developing therapeutics for HCC. However, until 2015 multiple phase III trials have been conducted, but failed to prove superior or sufficient efficacy as the first-line and second-line therapy for advanced HCC [Hsu CH et al, 2014]. The RESORCE trial is a randomized phase III study comparing regorafenib with a placebo in patients with HCC who had progressed sorafenib treatment [Bruix J et al, 2017]. Regorafenib, compared with a placebo, conferred a significant improvement of overall survival (OS) (median OS 10.6 months vs 7.8 months, with hazard ratio (HR) 0.62, 95% C.I. 0.50-0.78, P < 0.001). In Apr 2017, regorafenib was approved by the U.S. Food and Drug Administration for the treatment of HCC patients who have been previously treated with sorafenib. Immunotherapy especially blockade of immune checkpoints has recently demonstrated impressive clinical activities in multiple cancer types including HCC. CheckMate 040 is a phase I/II trial of nivolumab, a monoclonal antibody against PD-1, involving 262 HCC patients who have progressed at least one line of systemic therapy [El-Khoueiry AB et al, 2017]. Nivolumab at the dose of 3 mg/kg exhibited an objective response rate of 20% (95% CI 15-26) in HCC patients enrolled in the dose-expansion phase. Most recently, the phase III trial of lenvatinib versus sorafenib as first-line therapy for unresectable HCC was reported in 2017 Annual Meeting of American Society of Clinical Oncology (ASCO) [Cheng AL et al: 2017ASCO]. The study met its primary endpoint, showing that lenvatinib was non-inferior to sorafenib in OS (median OS 13.6 months vs 12.3 months for lenvatinib vs. sorafenib, with HR 0.92, 95% C.I. 0.79-1.02). Lenvatinib, compared with sorafenib, exhibited statistically significant improvements in time to tumor progression, progression-free survival, and response rate in unresectable HCC. The encouraging results of regorafenib, lenvatinib, and nivolumab have enriched our armaments for the treatment of HCC. Future studies are warranted to define the optimal use of these therapeutics, and to identify predictive and prognostic biomarkers for implementing personalized therapy for advanced HCC.