Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the second most lethal malignancy worldwide. In the Western world, HCC predominantly develops in patients with liver cirrhosis. Therefore, application of locoregional interventions and systemic agents should be based on an interdisciplinary evaluation, most importantly, taking the functional liver reserve into account. This review summarizes current treatment lines and novel strategies in the management of HCC. For the most part, randomized controlled trials and large meta-analyses are reported, with an emphasis on systemic therapies. Summary: In patients with limited hepatic disease and sufficient liver function, resection and local ablation are the most frequently employed curative locoregional therapies. Due to recurrence rates of up to 70% within 5 years and in patients with compromised liver function not amenable to these local modalities, liver transplantation remains superior in terms of tumor control and long-term survival. However, its applicability is limited because of the increasing gap between available donor organs and patients on the waiting list. Transarterial chemoembolization is commonly employed to bridge patients to transplantation and also serves as standard of care for patients not suitable for other local therapies. Recently, various phase 3 trials have reported a clinical benefit for the tyrosine kinase inhibitors lenvatinib, regorafenib, and cabozantinib in HCC. In addition, ramucirumab, an angiostatic antibody, also improves survival in second-line systemic therapy. This opens new avenues in the sequential application of treatment lines, and thus early response assessment is necessary to fully utilize the clinical impact of locoregional therapies and systemic therapies and to shift patients to further treatment lines before hepatic deterioration. Key Messages: Clinical decision-making in hepatocellular carcinoma is based on an interdisciplinary evaluation. Liver transplantation should always be considered as long-term curative treatment option, especially in T2 patients. In palliative treatment, early response assessment is required to advance patients to the next treatment line before decompensation.