Introduction: Since 2007 Sorafenib has represented the only approved drug for first-line treatment of advanced hepatocellular carcinoma (HCC). Lenvatinib, an orally active inhibitor of multiple receptor tyrosine kinases (VEGFR 1-3, FGFR 1-4, PDGFRa, RET and KIT), showed preclinical and clinical activity in the treatment of solid tumors, including HCC. Areas covered: In this review, we summarize the current therapeutic paradigm for the systemic treatment of advanced HCC, focusing on Lenvatinib pre-clinical and clinical development. Keywords 'Lenvatinib', ' Target therapy', 'REFLECT trial', 'Hepatocellular carcinoma', 'HCC', 'Sorafenib' were used for literature search on PubMed. Expert commentary: In Phase-III multicentric REFLECT trial Lenvatinib demonstrated a non-inferior overall survival (OS) compared to Sorafenib in the first-line treatment of advanced HCC, with a manageable toxicity profile, becoming a valid alternative option in the therapeutic repertoire of this disease. Nevertheless, the potential role of Lenvatinib in real-life clinical practice has still to be defined, especially in the light of the positive results that have been achieved with other new therapeutic agents (e.g. immunotherapy).