Lecture : After the success of sorafenib as a systemic therapy that can prolong the patient’s survival, there has been a long history of failure in discovering new drugs in hepatocellular carcinoma (HCC). However, all of a sudden, several drugs have recently been proven to be successful in prolonging the patient’s survival as a first-line or second-line therapy. Lenvatinib has been shown to be non-inferior to sorafenib in the first-line setting. It has different profiles of side-effects and accordingly represents an alternative to sorafenib. Regorafenib was proven to be effective as a second-line therapy for patients who could tolerate sorafenib but experienced disease progression during sorafenib treatment. It has similar safety profiles to sorafenib. Cabozantinib was approved as a second-line or third-line therapy for HCCs which progressed during sorafenib treatment. The study population included both sorafenib-tolerable and –intolerable cases. Ramucirumab was reported to be effective in sorafenib-failed patients with serum alpha-fetoprotein of ≥400 ng/mL. Two phase III clinical trials using immune-checkpoint inhibitors, nivolumab as a first-line therapy and pembrolizumab as a second-line therapy, failed to meet the predefined threshold for statistical significance. However, both drugs had higher objective response rates and durable anti-tumor activity compared to sorafenib or placebo, and were relatively tolerable. Recently, several studies have been being conducted using various combinations of immune-checkpoint inhibitors and anti-angiogenic drugs. In addition to its well-known role in angiogenesis, VEGF has several immune-suppressive effects in cancer microenvironments. In a recent interim results, combination of atezolizumab and bevacizumab showed significant improvements both in overall survival and progression-free survival compared with sorafenib (HR, 0.58 and 0.59, respectively), as a first-line therapy. Therefore, the paradigm of sequential treatment using sorafenib and then regorafenib, ramucirumab, or cabozantinib can be shifted in the near future.