Sorafenib is the first molecular targeted drug approved by the U.S. Food and Drug Administration (FDA) in advanced hepatocellular carcinoma (HCC). As an oral tyrosine kinase inhibitor, sorafenib inhibits tumor proliferation and angiogenesis by blocking the RAF/MEK/ERK signaling pathway and inhibiting vascular endothelial growth factor (VEGF) and PDGFR. Two international multicenter clinical studies, SHARP and ORIENTAL, confirmed the efficacy and safety of sorafenib in advanced HCC, initiating an era of molecular targeted therapy for HCC. The SHARP clinical study mainly enrolled HCC patients with hepatitis C virus infection in Europe and America, showing a median overall survival (mOS) of 10.7 and 7.9 months, a disease control rate (DCR) of 43% and 33%, and an imaging-based median time to progression (TTP) of 5.5 and 2.8 months in the sorafenib and placebo groups, respectively, with overall survival (OS) prolonged by 44% and TTP prolonged by 73%. The ORIENTAL trial, conducted in the Asia-Pacific region in hepatitis B virus-infected patients with advanced HCC, showed an mOS of 6.5 and 4.2 months, a DCR of 35% and 16%, and an imaging-based median TTP of 2.8 and 1.4 months in the sorafenib and placebo groups, respectively, with OS prolonged by 47% and TTP prolonged by 74%.