Systemic autoimmune diseases are characterized by the development of antinuclear autoantibodies. In order to understand the immunologic events leading to the development of such antibodies, knowledge of mechanisms of immune tolerance to nuclear antigens is required. By utilizing adoptive T-cell transfer strategies with transgenic mouse models expressing nuclear neo-self antigens, T-cell tolerance to the lupus-related nuclear antigens human La and nRNP A has been demonstrated. These findings also indicate the existence in normal animals of autoreactive B cells continuously presenting nuclear antigen, suggesting that nuclear antigens are not sequestered from the immune system. Investigations of CD4+ T-cell tolerance to non-nuclear antigens have revealed a number of mechanisms that protect the host from autoreactivity, including autoreactive T-cell deletion, regulatory T-cell development and anergy induction. Recent studies using T-cell receptor and neo-self nuclear antigen transgenic mice are revealing the importance of such mechanisms in maintaining tolerance to nuclear antigens. Mechanisms of tolerogenic antigen presentation, identification of tolerogenic antigen source(s) and the pathways leading to loss of tolerance to nuclear antigens in systemic autoimmune disease states are currently being sought.