Immune tolerance is known as the state of an active, highly regulated unresponsiveness of the immune system to self-antigens or against a particular antigen that can induce an immune response in the body. Immunological tolerance is broadly categorized as (1) central tolerance and (2) peripheral tolerance mechanisms that provide and maintain the self-tolerance. Central tolerance is achieved through the mechanism of negative selection by newly developing lymphocytes in primary lymphoid organs tolerant to self-antigens. Peripheral tolerance describes the mechanisms that prevent autoreactive lymphocytes from initiating potentially harmful immune responses against the body's own antigens, or food and commensal organisms through anergy, deletion, or development of induced Tregs. This chapter will review the importance of immunological tolerance in cancer, autoimmunity, and transplantation.