Background: Hepatocellular carcinomas (HCCs) rank among the most common cancers worldwide, with a rising incidence in Western countries. HCCs are characterized by a pronounced chemoresistance. Materials and methods: The work is based on a selective literature review that reflects the current clinical context and promising future developments. Results: The tyrosine kinase inhibitor sorafenib is the current standard treatment for advanced HCCs in patients with preserved liver function. After the approval of sorafenib in 2007, none of the substances tested in large phase III studies until 2016 showed a survival benefit in first- and second-line treatment. In 2016, the tyrosine kinase inhibitor regorafenib showed a meaningful improvement in overall survival after failure of sorafenib therapy and thus extended the spectrum of active substances in a second-line setting. In addition, the non-inferiority of lenvatinib in comparison to sorafenib opened another therapeutic first-line option. Positive results with cabozantinib and ramucirumab as second-line treatment have recently been presented. The checkpoint inhibitors nivolumab and pembrolizumab have proven promising and initiated the era of immune oncology in HCC, which will probably gain increasing importance for mono- as well as combination therapy. Conclusion: After nearly 10 years of stagnation in the field of systemic treatment, several active substances are now available for the treatment of HCC. Thus, for the first time, a sequential approach is both possible and feasible, which will ultimately improve the survival of HCC patients.