The host antitumor immune response in patients with advanced melanoma is compromised with a bias towards tumor immune tolerance and a tumor microenvironment that facilitates disease survival and progression. Overcoming tumor-induced immune suppression has been one of the most significant advances in cancer therapy, making a cure an ever closer and achievable goal. Immunotherapeutic strategies in melanoma have been built upon the immunomodulatory qualities and the early successes of interferon-α in the melanoma adjuvant setting and interleukin-2 in the treatment of inoperable advanced melanoma. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opened the doors for novel agents and combinations that may potently overcome tumor tolerogenic mechanisms. Recent data with immune anti-CTLA4 and anti-PD1 monoclonal antibodies have moved the clinical management of advanced melanoma into a new era, an era of long-term survival and potential cures.