Abstract Hepatocellular carcinoma (HCC) is prevalent worldwide with suboptimal therapeutic outcomes. The advancement of therapeutic options and the development of new systemic therapies expand the armamentarium to tackle HCC. Treatment options should be provided based on the hierarchy of efficacy in a multidisciplinary perspective, instead of the traditional stage‐guided scheme. In advanced HCC, lenvatinib has a comparable efficacy as sorafenib for the first‐line therapy of HCC; while regorafenib, cabozantinib, and ramucirumab have been approved as second‐line therapy after the failure of sorafenib. Immune checkpoint inhibitor therapy prolongs response rate and survival and enables long‐term cure. Atezolizumab plus bevacizumab is superior to sorafenib as the first‐line therapy for advanced HCC. Several emerging regimens by the combination of various systemic therapies are currently under clinical trials. Systemic therapy may be used in the neoadjuvant, adjuvant or even as initial therapy for intermediate‐stage HCC. The paradigm shift of HCC treatment will improve patient outcomes.
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