There has been much recent attention on immunotherapy for cancer due to the promising results of several randomized phase-III trials. The management of metastatic melanoma in particular is a significant clinical challenge, and it has long been a desired target of immunotherapies due to evidence of the importance of host immune responses. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) serves as a negative regulator of immunity. Recent trials administering fully-human anti-CTLA-4 monoclonal antibodies to patients with melanoma have demonstrated survival benefits. However, treatment with anti-CTLA-4 antibodies is not without potential toxicities. Autoimmune side-effects, such as diarrhea, bowel inflammation and dermatitis, were the most commonly reported. To build upon the activity seen with anti-CTLA-4 antibodies, both in toxicity and efficacy profiles, there has been significant interest in investigating combinations with vaccination strategies. In recent trials, patients who were vaccinated with autologous tumor cells engineered to secrete granulocyte–macrophage colony-stimulating factor, and were then infused with anti-CTLA-4 antibodies, demonstrated clinically-significant antitumor immunity without grade-3 or -4 toxicity in most patients. These data demonstrate how manipulation of immune regulation has produced patient benefits, and this area is a rich avenue for future investigation.