Self-antigens are the most relevant and abundant antigens to which the host's immune system must be tolerant. Induction and maintenance of tolerance to self-antigens is mediated by several mechanisms that prevent inappropriate damage to normal tissues. However, these same mechanisms may impose potential barriers for the full development of effective immune responses against antigens expressed by tumors. A critical issue in tumor immunology is whether antigen presented by a progressively expanding tumor cell population results in T-cell tolerance. Utilizing a T cell receptor transgenic mice specific for a model tumor antigen expressed on a B-cell lymphoma, recently we have obtained direct evidence supporting the existence of tumor-induced antigen-specific tolerance. A better identification and understanding of the factor(s) involved in tumor-induced tolerance has clear implications for the development of novel cancer immunotherapies aimed at safely breaking tolerance, for example, releasing the brakes on antitumor immune responses while still limiting the induction of undesirable autoimmune responses.