The immune system can attack almost any given organ in a very specific and directed fashion. The endocrine system appears to be particularly vulnerable to this kind of insult. Which endocrine organs are most susceptible and why? Genetic studies and animal models have revealed some commonalities for these diseases. The MHC locus appears to help control not only susceptibility to disease but also which endocrine organs are attacked. Autoimmune thymectomy models have revealed suppressor cell populations, which are being intensely sought after as a protective mechanism against endocrine autoimmunity. Finally, the recent cloning of the causative gene for autoimmune polyglandular syndrome type I, called AIRE, has brought central tolerance back into focus as an important mechanism in these endocrine diseases.