Melanoma is the most aggressive skin cancer whose incidence is increasing in western countries. Among novel treatments, immunotherapy has shown promising results for melanoma in recent years. Interferon-α and interleukin-2 are two cytokines, used in many old and recent studies to treat melanoma alone or in combination with other options as first-line treatment or adjuvant therapy. These cytokines proved to be effective for melanoma treatment; however, they also caused high-grade immune-related adverse effects (irAE), which need to be carefully managed. Immune checkpoint inhibitors also showed great antitumor effects. Blocking the cytotoxic T lymphocyte antigen (CTLA-4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) induced a high response rate (RR) in many studies, but the rate of high-grade irAEs, especially in the skin and liver, was also considerable. In addition to the abovementioned methods, several cancer vaccine strategies as well as adoptive cell therapy (ACT), almost a new method that resulted in improved overall survival (OS) in hematologic malignancies, are being tested for melanoma. In this chapter, we will review the efficacy of various immunotherapeutic methods for patients with melanoma and discuss their potential adverse effects.