The recent cloning and identification of a variety of regulatory and counter-regulatory molecules on T cells and antigen presenting cells has led to the development of antibodies and other molecules that either stimulate or abrogate these immune functions. Patients with autoimmune disease, graft rejection and cancer might benefit from the ability to manipulate immune regulatory pathways. The first demonstration of clinical benefit by modulation of immune regulation in cancer involves the use of human antibodies against cytotoxic T lymphocyte antigen 4. Murine preclinical studies suggested that cytotoxic T lymphocyte antigen-4 abrogation would provide clinical benefit after an antitumor vaccination. Early trials of this antibody in patients with melanoma have shown antitumor activity with and without vaccines that is associated with a state of autoimmunity. Surprisingly, the reversal of the state of autoimmunity induced by cytotoxic T lymphocyte antigen 4 antibodies by the use of corticosteroids does not eliminate clinical benefit.