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Hepatocellular carcinoma (HCC) is a complex disease, since both choice of treatment and prognosis depend not only on tumor-specific but also on liver-related characteristics. Therefore, a multidisciplinary approach in specialized clinics is required for the optimal management of HCC patients. Almost half of patients present with advanced-stage tumor with no curative therapeutic options. According to international guidelines, palliative systemic therapy is recommended in these patients. The multikinase inhibitor sorafenib was the first drug to show antitumor efficacy and was the only approved treatment for almost a decade, as several other agents failed to improve patient survival. In recent years, treatment practices have changed with lenvatinib as another first-line treatment choice and regorafenib, cabozantinib, and ramucirumab as second-line therapeutic options. However, only patients with preserved liver function (Child-Pugh-Turcotte [CPT]-A) were enrolled in these studies and are consequently suitable for these drugs. After promising phase‑1 and phase-2 studies, subsequent phase‑3 trials evaluating the immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab have failed to demonstrate a significant improvement in patient survival. Ongoing trials are evaluating the combination of ICIs with tyrosine kinase inhibitors or vascular endothelial growth factor (VEGF) inhibitors. Recently, in a phase‑3 trial, the combination therapy atezolizumab and bevacizumab led to a significantly improved overall survival compared to sorafenib in the first-line setting. Further studies are needed to determine how best to select between the growing number of therapeutic options.