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For many years, sorafenib has been the only approved systemic treatment for advanced hepatocellular carcinoma (HCC). For over a decade, randomized controlled trials exploring the efficacy of new drugs both in first- and second-line treatment have failed to prove any survival benefit. However, in the past few years, several advances have been made especially in pretreated patients; phase III trials of regorafenib, cabozantinib, and ramucirumab in patients with elevated α-fetoprotein have demonstrated efficacy in patients progressing after or intolerant to sorafenib. In addition, early phase I and II trials have shown promising results of immunotherapy alone or in combination with tyrosine-kinase inhibitors or monoclonal antibodies in the same setting of patients. In this review, we will discuss the evidence on second-line options for HCC, focusing on the latest results that are currently refining the treatment scenario., Competing Interests: Disclosure and potential conflicts of interest: Donatella Marino, Clizia Zichi, Marco Audisio, and Elisa Sperti report no conflict of interest. Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Lilly, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, and Janssen. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at http://www.drugsincontext.com/wp-content/uploads/2019/03/dic.212577-COI.pdf