Summary: Recent developments and new approvals in targeted agents and immunotherapy have changed the melanoma therapy in metastatic setting and they were currently implemented for adjuvant treatment in high risk disease. The prognosis of the patients with melanomas at IIBIV stage even after a complete resection is diverse and often connected with a high risk of disease recurrence. Thus, immunotherapy with immune checkpoint inhibitors (anti-PD-1: nivolumab or pembrolizumab) and molecularly targeted treatment with BRAF and MEK inhibitors (dabrafenib with trametinib in BRAF-mutated cases) significantly decreased risk of relapse and as adjuvant therapy after resection in stage III disease. Additionally nivolumab is approved also for postoperative therapy in stage IV disease and pembrolizumab (in US) as adjuvant therapy in stage IIB-C disease. Moreover, the outcomes of the clinical studies with use of neoadjuvant systemic treatment in patients with loco-regionally advanced melanomas are very promising giving the chance to change paradigm of therapy in this setting.