Background: Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer
death in men worldwide, and is extremely resistant to chemotherapy. Sorafenib is a multi-targeted
kinase inhibitor and a first-line systemic drug for advanced HCC, but demonstrates limited survival
benefits. Therefore, investigating underlying mechanisms and seeking potential strategies to enhance
its efficacy, or second-line treatments after the failure of sorafenib, have been launched. Methods: Research
and content related to sorafenib and HCC were retrieved from online data resources including
Pubmed, Embase, Cochrane and Clinicaltrial.gov. The article emphasizes on the clinical application of sorafenib in the
management of HCC. Results: The present article reviews the epidemiology and pathogenesis of HCC, history of systemic
treatments, molecular targets of sorafenib and its development history, Barcelona-Clinical Liver Cancer (BCLC) staging
system, analysis of completed and ongoing clinical trials including single-agent and combinational trials, the major guidelines,
mechanisms for drug resistance and corresponding strategies, and future prospects. Conclusion: The mechanisms for
hepatocarcinogenesis are very complicated and no single pathway or molecule has been shown to play a decisive role.
Sorafenib is undoubtedly a great progress, but is yet not a precision-guided weapon for HCC. Further exploration of
mechanisms by using modern computational technology and optimizing current staging system may be the ways to
achieve the final goal of personalized therapy for HCC, but these efforts rely on global collaboration and disclosure of
data, particularly those from clinical trials.