Key points include the following: (i) lenvatinib suppressed sorafenib-resistant HCC cell proliferation, mainly by inducing G1 cell cycle arrest; (ii) the underlying advantage of lenvatinib in overcoming sorafenib resistance may occur through the FGFR4-ERK signaling pathway; (iii) along with HBV DNA, poor autophagic responsiveness may be a contributing factor toward partial cross-resistance; and (iv) miRNA alterations may contribute to the inhibition of sorafenib-resistant HCC cell growth and angiogenesis (Figure 9). Here, FGFR4 is linked to hepatocellular carcinoma.