Hepatocellular carcinoma (HCC) is one of the most common and most lethal cancers worldwide. Treatment of patients with HCC is complicated by the underlying liver disease in up to 80% of all cases. Interdisciplinary and multimodal treatment strategies are essential for successful therapy. Established therapies include surgical interventions (liver transplantation, resection), local ablative therapies (e.g., microwave or radiofrequency ablation), and locoregional therapies (e.g., transarterial chemoembolization [TACE] and selective internal radiotherapy [SIRT/TARE]). Moreover, there are emerging opportunities for systemic therapies. While the multityrosine kinase inhibitor sorafenib has been the only agent approved for patients with unresectable HCC for almost a decade, there are now additional systemic treatment options including the tyrosine kinase inhibitors (TKIs) lenvatinib, regorafenib, and cabozantinib as well as the VEGF-receptor inhibitor ramucirumab. To date, immune checkpoint inhibitor monotherapies have failed to show an overall survival benefit, but according to recent data combined immunotherapy/VEGF inhibition has shown superior activity in first-line treatment compared with sorafenib. The advent of numerous novel systemic agents offers a variety of combination opportunities. Combinations of systemic agents with locoregional treatments in palliative and potentially curative settings are currently being investigated. Today, treatment of patients with HCC is more challenging than ever owing to the multiple therapeutic options available, demanding strict multidisciplinary cooperation in the treatment selection process. There is an urgent need for clinical studies in order to further optimize the therapy sequence and to identify efficacious mono- and combination therapies.