Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.