Immune tolerance reflects the absence of immune reactions to self-antigens (natural tolerance) or exogenous antigens, at least in experimental models (acquired tolerance). It results in part from central mechanisms leading to the elimination or deletion of auto-reactive B or T cell clones by apoptosis in primary lymphoid organs. In the periphery, this is reflected by more-or-less reversible states of anergy, which arise from a time or spatial discordance between the different signals required for lymphocyte activation, or from a network of interactions between lymphocytes leading to the production of antagonistic signals. The reversibility of anergy-inducing mechanisms, a deregulation of the production of certain cytokines, or incomplete clonal deletion mechanisms could explain the emergence of autoimmune diseases by a rupture of self-tolerance. As these mechanisms are not fully understood, clinical induction of tolerance by the use of nonspecific immunodepressive agents is not yet possible.