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Host defense is dependent on the appropriate induction of immune responses. A central concept in immunology is the ability of the immune system to differentiate foreign from self-antigens. The failure of the immune response to recognize foreign pathogens can result in infection and disease in the host. The inappropriate response of the immune system to self-antigens is equally problematic, leading to autoimmune disease. Central and peripheral tolerance mechanisms control self-reactive T-cell responses and protect peripheral tissues from autoimmune attack. This review examines the roles of B7/CD28 family members, which can augment or antagonize T-cell receptor signaling, in the regulation of central and peripheral T-cell tolerance. We also discuss how B7/CD28 pathways influence both T-cell-intrinsic and -extrinsic mechanisms of regulation.