BACKGROUND: Advanced hepatocellular carcinoma (HCC) portends a poor prognosis; however recent advances in first-line and second-line treatment options should yield significant improvements in survival. AIM: To summarize the evolving landscape of treatment options for patients with advanced HCC. METHODS: We reviewed published clinical trials conducted in patients with advanced HCC published in PubMed or presented at national conferences. RESULTS: Sorafenib was approved for treatment of unresectable HCC in 2007 and remained the only therapy with proven survival benefit in advanced HCC for several years. Lenvatinib, another tyrosine-kinase inhibitor, was recently shown to have non-inferior survival vs sorafenib and is another first-line treatment option. The tyrosine-kinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second-line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second-line setting among patients with AFP ≥ 400 ng/dL. Phase II data highlight potential durable objective responses with immune checkpoint inhibitors, prompting conditional FDA approval of nivolumab and pembrolizumab in the second-line setting; however, recent phase III data have failed to demonstrate improved survival compared to other treatment options. Ongoing trials are evaluating combination immune checkpoint inhibitor and immune checkpoint inhibitors with tyrosine-kinase inhibitors or VEGF inhibitors in hopes of further increasing objective responses and overall survival in this patient population. CONCLUSION: There are several first-line and second-line therapeutic options available for patients with advanced HCC. Further studies are needed to determine how best to select between and sequence the growing number of therapeutic options.