Background: The medical therapy of inoperable malignant melanoma has changed dramatically over the last few years. Objectives: The purpose of this article is to summarize the current state of systemic medical treatment of malignant melanoma. Materials and methods: Clinical studies and guidelines in the therapy of malignant melanoma are reviewed. Results: Medical therapy of inoperable melanoma changed due to developments in immunotherapies (checkpoint inhibitors) and molecular-targeted therapies (BRAF and MEK inhibitors). Checkpoint inhibitors are antibodies administered as infusions every 2–3 weeks, blocking the checkpoints PD-1 or CTLA-4, thus, preventing downregulation of the immune system. BRAF and MEK inhibitors are small molecules, they are given orally and block a certain signaling pathway in tumor cells. The activation of this pathway has to be demonstrated by molecular analysis of tumor tissue first. This strategy is currently registered for 40–50 % of melanomas harboring a BRAF V600 mutation, while the combination of a BRAF plus MEK inhibitor has been proven more efficient than a BRAF inhibitor alone. Discussion: A fascinating development has started in the melanoma field due to immunotherapeutic and molecular-targeted treatment strategies. The continuation of this development needs further clinical and translational studies. This includes particular clinical studies with the new substances in the adjuvant situation, and sequences and combinations in the metastatic setting. Translational studies are needed to develop biomarkers for response and side effects.