Background <p>The introduction of adjuvant treatment with immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors has significantly improved recurrence-free (RFS) and distant metastasis-free survival (DMFS) for melanoma patients. However, a significant improvement in overall survival (OS) has currently not been demonstrated in phase III clinical trials. Furthermore, not all patients benefit from adjuvant systemic therapy. For these patients, perioperative and neoadjuvant systemic therapy represent a promising new therapeutic approach.</p> Objective <p>In this review, we explore the origins of neoadjuvant and perioperative therapy for melanoma therapy and describe the current state of clinical trials. We also address the opportunities and hurdles for the integration of these novel therapy concepts into routine clinical practice.</p> Results <p>Current studies have shown an improved RFS and DMFS for patients with melanoma ≥ stage IIIB treated with neoadjuvant and perioperative systemic therapies compared to adjuvant systemic therapy. Pathologic response is proving to be an excellent prognostic marker for the success of neoadjuvant therapy. ICI appears to be superior to treatment with BRAF/MEK inhibitors in the neoadjuvant setting and therefore constitutes the current preferred neoadjuvant treatment strategy.</p> Discussion <p>The efficacy of perioperative and neoadjuvant systemic therapies in melanoma patients suggests that these therapy concepts should be integrated into routine patient care. However, neoadjuvant and perioperative therapies are only available for patients with resectable metastases, and the current lack of approval represents an obstacle to the use of neoadjuvant systemic therapies in routine care in Germany. </p>