<jats:p>Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (<jats:styled-content style="fixed-case">HCC</jats:styled-content>). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of <jats:styled-content style="fixed-case">HCC</jats:styled-content> on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks <jats:styled-content style="fixed-case">HCC</jats:styled-content> cell proliferation by inhibiting <jats:styled-content style="fixed-case">BR</jats:styled-content>af and <jats:styled-content style="fixed-case">R</jats:styled-content>af1/c‐<jats:styled-content style="fixed-case">R</jats:styled-content>af serine/threonine kinase phosphorylation in the mitogen‐activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing el<jats:styled-content style="fixed-case">F</jats:styled-content>4<jats:styled-content style="fixed-case">E</jats:styled-content> phosphorylation and downregulating <jats:styled-content style="fixed-case">M</jats:styled-content>cl‐1 levels in tumor cells. Third, sorafenib prevents tumor‐associated angiogenesis by inactivating vascular endothelial growth factor receptors (<jats:styled-content style="fixed-case">VEGFR</jats:styled-content>‐2 and ‐3) and the platelet‐derived growth factor receptor‐β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable <jats:styled-content style="fixed-case">HCC</jats:styled-content>. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in <jats:styled-content style="fixed-case">HCC</jats:styled-content> patients.</jats:p>