Tolerance against self-antigens is achieved in the lymphopoietic differentiation in early life, when highaffinity self-reactive lymphocytes are deleted in the primary lymphoid organs, thymus, and bone marrow. Second, in the periphery, there is activity of a subset of T lymphocytes, T regulatory cells (Tregs), which are dedicated to regulatory function expressing the CD4 and CD25 surface markers and the transcription factor forkhead box P3 (FOXP3). Additional backups along the maturation process of lymphocytes are described, limiting the induction and expression of autoimmunity. These regulatory mechanisms include apoptosis pathways, cytokines and their receptors, chemokine signaling, T cell-T cell interactions, and intracellular signal transduction. Accordingly, loss of self-tolerance could involve multiple faults, most of which are of genetic origin.