PURPOSE OF REVIEW: To provide an overview of the mechanisms of autoimmunity associated with primary immunodeficiencies. RECENT FINDINGS: Over the past several years, new concepts of the relationship between primary immunodeficiencies and autoimmunity have developed that promise to illuminate the mechanisms by which alterations in the same gene may alternately, or sometimes concomitantly, lead to increased susceptibility to infection and loss of self-tolerance. A common pathway in the process leading to autoimmunity involves gene defects that permit effector T-cell development in the absence of sufficient regulatory T-cell function. Conversely, gene defects that primarily lead to autoimmunity may impair host defense by neutralizing key elements of immunity. The production of neutralizing antibodies against cytokines comprises a newly recognized mechanism in which autoimmunity may lead to immunodeficiency. SUMMARY: Autoimmunity has long been known to be a part of the presenting symptoms and clinical course of many primary immunodeficiencies. This review will provide an overview of the new concepts regarding the complex relationship between the genetic immune deficiencies and autoimmunity. The mechanisms by which immunodeficiency may lead to autoimmunity or, in some instances, by which autoimmunity produces immunodeficiency can provide important insights into the underlying pathogenic processes and ultimately better diagnosis and treatment for the patient. © Lippincott Williams & Wilkins.