Surgical excision is the treatment of choice for early stage melanoma, and this strategy is initially curative for the vast majority of patients. However, only approximately 40-60% of high-risk patients who undergo surgery alone will be disease-free at 5 years. These patients will ultimately experience loco-regional relapse or relapse at distant sites. The main aim of adjuvant therapies is to reduce the recurrence rate of radically operated patients at high risk and to potentially improve survival. Recent practice changing results with immune checkpoint inhibitors and targeted therapies have been published in stage III/IV melanoma patients, after surgical complete resection, and have dramatically improved the landscape of adjuvant therapy. Interferon-α, ipilimumab, and more recently anti-programmed cell death protein-1 antibodies and BRAF inhibitors plus MEK inhibitors have been approved in the adjuvant setting by the US Food and Drug Administration; similarly, the same drugs are approved by the European Medicines Agency with the exception of ipilimumab. A completely new scenario is emerging in the neoadjuvant setting as well: in locally advanced or metastatic disease, patients may partially respond to neoadjuvant therapy and become virtually resectable with systemic control of disease. This review summarizes the current state of the field and describes new strategies tracing the history of adjuvant therapy in melanoma, with a view on future projects.