Metastatic melanoma is a disease associated with poor prognosis, with a median survival reported to range from 6 to 9 months. Patients who are not candidates for surgical resection have an even worse expected survival. This is largely due to the lack of effective chemotherapeutic regimens and has led to the investigation of alternative treatment strategies including immunotherapy. Although melanoma is felt to be an immunogenic tumor and has been associated with the development of spontaneous tumor-specific immune responses in patients, the implementation of vaccine-based treatment has had limited success. Because the administration of a melanoma-specific vaccine alone has not been sufficient to generate robust and reproducible clinical responses, investigators are currently pursuing additional methods to augment antimelanoma immune responses by optimizing T-cell activation. T-cell activation requires both antigen presentation to the T-cell receptor and a second signal mediated by CD80 and CD86 on antigen-presenting cells and CD28 on the T cell. Ligand binding to CD28 on the T-cell surface leads to T-cell proliferation and expression of activating cytokines such as interleukin-2. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitory protein expressed on T cells, competes for the same ligands as CD28 and modulates T-cell activation. Because CTLA-4 has a significantly higher binding efficiency than CD28, CTLA-4 is critical in maintaining immune tolerance to self-antigens and may also limit responses to tumor antigens and vaccine therapy. CTLA-4 blockade either alone or in combination with melanoma-specific vaccines has been explored as a potential means to treat advanced stage melanoma. In this article, we review the spectrum of clinical trials involving CTLA-4 blockade and also review recent correlative studies attempting to elucidate the potential mechanisms by which CTLA-4 blockade achieves its therapeutic effects.