Exploring effective therapeutic drugs and means is of great significance in the treatment of primary liver cancer. In recent years, with the continuous development of molecular biology technology, the basic and clinical researches on the pathogenesis and tumor progression of hepatocellular carcinoma have made remarkable progress, and new molecularly targeted drugs are emerging, including epidermal growth factor receptor inhibitors, anti-angiogenic drugs and multikinase inhibitors, etc. Biologically targeted therapy has gradually become a new choice and hope for patients with primary hepatocellular carcinoma. The research progress is briefly introduced as follows. Multi-target Raf kinase inhibitors Many steps in the process of tumor growth, development, and metastasis are mediated by the signaling pathway starting from tyrosine kinase receptor activation. A variety of tumor cells have up-regulation of the Raf/MEK/ERK transduction pathway, which transmits signals from the outside of the cell into the nucleus through specific cascade phosphorylation of Ras, Raf, MEK and ERK. As a downstream substrate of Raf kinase, activated MEK phosphorylates ERK, which regulates cellular functions by acting on multiple substrates. Preclinical studies have shown that growth factors such as VEGF, PDGF-β, epidermal growth factor (EGF), and transforming growth factor-α (TGF-α), once bound to their cognate receptors, activate the Raf/MEK/ERK pathway by autophosphorylation of receptor tyrosine kinases. Over-activation of the Raf/MEK/ERK pathway results in accelerated cell proliferation and prolonged cell survival, leading to tumor formation and progression. The kinase has three isozymes, A-Raf, B-Raf, and Raf1 (also known as C-Raf), all of which are closely related to the regulation of cell proliferation, differentiation, survival, attachment, and angiogenesis. Among them, Raf1 is expressed in most human tissues and is likely to inhibit apoptosis by regulating apoptosis-related factors, and is therefore important in tumor formation and development. Raf1 is mainly found in vascular-rich solid tumors (e.g., hepatocellular carcinoma). These include VEGFR-2, VEGFR-3, PDGFR-β, and c-kit and Flt-3, which are associated with tumor growth. The results of several clinical studies have shown that sorafenib has broad-spectrum anti-tumor effects, which can block the Raf/MEK/ERK pathway in hepatocellular carcinoma cells, inhibit the neovascularization of hepatocellular carcinoma cells and induce cell apoptosis. The phase II clinical trial of et al. treated 137 patients with progressive hepatocellular carcinoma that could not be surgically resected with sorafenib monotherapy (400 mg,bid). Results showed that 2.2% and 5.8% of patients achieved partial or mild remission after treatment, respectively; 33.6% of patients had stable disease for ≥16 weeks; median time to progression (TTP) and overall survival (OS) were 4.2 months and 9.2 months, respectively; and grade III/IV adverse events mainly included fatigue (9.5%), diarrhea (8.0%), and hand-foot syndrome (5.1%). syndrome (5.1%). The trial also found that TTP was longer in those whose tumors expressed high levels of pERK prior to treatment, suggesting that pERK may be a biomarker for the efficacy of sorafenib therapy. The patient survival data in this phase II trial were comparable to previous cytotoxic drug trials for hepatocellular carcinoma. Although there may be selective bias in patient enrollment, the large sample size of this trial increases the reliability of the results. In light of the results of these phase II trials, several phase III randomized clinical trials have been initiated. Among them, the SHARP study was an international multicenter, randomized, double-blind, placebo-controlled phase III clinical study that enrolled 602 patients who were randomized in a 1:1 ratio to either the sorafenib 400 mg,2/day group (n=299) or the placebo group (n=303). Patients were stratified by: large vessel invasion (MVI) (portal vein) and/or extrahepatic metastases (EHS), ECOG physical status score, and geographic region. The results of the study showed that sorafenib significantly prolonged overall survival (OS) in patients with advanced hepatocellular hepatocellular carcinoma (10.7 months vs. 7.9 months).