Hepatocellular carcinoma (HCC) is the fourth most common neoplasm and the third leading cause of cancer-related death worldwide. Tremendous effort has been made during the past several years in understanding the molecular mechanisms governing the pathogenesis and progression of HCC. Recent studies indicated that c-Jun N-terminal kinase 1 (JNK1), but not JNK2, played pivotal role in the expression of the key signature genes and the prognostic outcomes of HCC. Accordingly, we believe that targeting JNK1 is not only mechanistically sound but also clinically feasible for the treatment of HCC.