This chapter explores systemic treatment strategies for cutaneous melanoma across neoadjuvant, adjuvant, and Stage IV settings. Neoadjuvant therapy aims to reduce tumor burden pre-surgery, primarily using immune checkpoint inhibitors like nivolumab plus ipilimumab, showing promising response rates. Adjuvant therapy, post-resection, leverages immunotherapy (e.g., nivolumab) and targeted therapies (e.g., dabrafenib plus trametinib) to prevent recurrence in high-risk patients, improving relapse-free survival. Stage IV systemic treatment addresses metastatic disease, employing immunotherapy (nivolumab, pembrolizumab) and targeted mitogen-activated protein kinase (MAPK) pathway inhibitors (dabrafenib plus trametinib) for BRAF-mutant cases, while BRAF wild-type patients benefit from nivolumab-relatlimab or combination therapies. Tables summarize key regimens, efficacy, and toxicities. Content aligns with clinical guidelines, with updates on emerging therapies like tumor-infiltrating lymphocytes (TIL). These approaches enhance survival and treatment-free intervals, tailored to mutation status and disease stage.