Immunologic tolerance is a state of unresponsiveness that is specific for a particular antigen. The immune system has an extraordinary potential for making T cell and B cell that recognize and neutralize any chemical entity and microbe entering the body. Certainly, some of these T cells and B cells recognize self-components; therefore, cellular mechanisms have evolved to control the activity of these self-reactive cells and achieve immunological self-tolerance. The most important in vivo biological significance of mechanisms regulating self-tolerance is to prevent the immune system from mounting an attack against the host's own tissues resulting in autoimmunity. This review summarizes recent developments in our understanding of T-helper cell tolerance and discusses how the new findings can be exploited to prevent and treat autoimmune diseases, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.