Autoimmunity implies disturbances at several levels of the immune control. Self-tolerance and discrimination between self and non-self synergize to avoid the development of autoimmunity. Negative selection in the thymus, the transcription factor AIRE, CD4+CD25+ regulatory T cells, and dendritic cells cooperate to produce and maintain tolerance. Cytokines modulate deriving immune processes and influence the local micro-environment. Multiple mechanisms are involved in tolerance breakdown: genetic factors (major histocompatibility complex haplotypes, polymorphisms in the cytotoxic T lymphocyte antigen gene and epigenetic alterations), environmental factors (mainly infections), impaired apoptosis, and the emergence of autoreactive naive lymphocytes. These events may be involved in the pathogenesis of endocrine diseases at several levels.