Advanced melanoma is a devastating disease with a very poor overall prognosis. There are only two agents that are approved by the FDA for use in patients with metastatic melanoma: dacarbazine and IL-2. Both agents have an overall response rate well below 20%, with only rare long-term responders noted. Metastatic melanoma is known to be one of the most resistant cancers to a plethora of treatment modalities, such as single-agent and combination chemotherapy, chemoimmunotherapy and immunotherapy with a host of immune stimulators. Indeed, researchers worldwide have recognized the lack of effective therapies and have refocused their efforts on developing novel and cutting-edge strategies of treatment. This is based on an improved understanding of the complex interactions that occur within the tumor microenvironment, and the central role that the host immune system plays in the surveillance of cancer. This review summarizes the recent results of novel immunotherapeutic regimens and focuses on cutting-edge modalities of treatment that encompass new lines of thinking in the war against cancer and, in particular, melanoma.