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For years, interferon alpha was the sole option in the adjuvant treatment of patients with completely resected melanoma with lymph node metastases and a high risk of disease recurrence, albeit being associated with a relatively low efficacy combined with significant toxicities. After the advent of immunotherapy and targeted therapy in locally advanced or metastatic melanoma at the beginning of the last decade, these therapeutic approaches have meanwhile also shown superior efficacy compared to previously used treatments or observation in the context of adjuvant therapy. Hence, adjuvant targeted or anti-PD1-antibody-based immunotherapy was incorporated into routine clinical practice to reduce the risk of tumor recurrence in affected patients in early 2018. Moreover, modern melanoma therapies are increasingly being investigated in a neoadjuvant setting in analogy to other solid malignancies. Considering the promising results reported so far, neoadjuvant immunotherapy might potentially become the treatment of choice in high-risk melanoma patients with macrometastatic disease in the near future.