Regulatory T cells play essential roles in inducing self-tolerance by suppressing immune responses against self such as autoantigens or non-self-antigens such as tumor and pathogenic antigens. Despite the importance of CD4(+) regulatory T cells in many immune-related diseases, their antigen specificity and suppressive mechanisms remain elusive. This review discusses the natural ligands and their potential roles of tumor-specific CD4(+) regulatory T cells in cancer therapy.