A number of studies have shown that melanoma is a particularly immunogenic tumour, at least in the early stages of its development. A range of clinical phenomena also suggests that immune responses play an important role in the natural history of the disease, including the total or partial regression of primary melanomas associated with lymphoid infiltrates. Immunization with a variety of vaccines can increase immune responses to melanoma, but whether this is of therapeutic benefit remains unclear. Various trials of melanoma vaccines have shown benefits but their significance has been marginal to date. Two trials have actually shown an adverse effect on survival. Stimulation of immune responses by blocking down-regulatory mechanisms in the immune system has evolved as a potential therapeutic approach following studies that have shown that immune responses are finely regulated by a series of receptors and ligands on lymphocytes and antigen presenting cells. The best studied of these approaches is the blockade of the cytotoxic T-lymphocyte antigen 4 receptor on T cells, which allows the generation of more effector cells for longer periods. Agents targeting this receptor have shown promising results and continue to be studied.