The immune repertoire of normal, healthy individuals contains autoreactive T cells and natural antibodies that, under normal conditions, are controlled, either through central tolerance or by the activity of immunoregulatory T cells to prevent the onset of autoimmune diseases. Over the years, several types of immunoregulatory T cells have been identified. These include natural CD4+CD25+Foxp3+T (Treg) cells and type 1 NKT cells, which develop in the thymus, as well as acquired immunoregulatory T cells, such as type 1 cells (Tr1), Th3 cells, Ts cells and anergic CD4 T cells, which all appear to be products of peripheral immune activation. While little is understood about the genetics of most types of immunoregulatory T cell, detailed information on the genetic control of NKT and Treg cells is now available and may contribute significantly to our understanding of the aetiology of autoimmune disease. (C) 2008 Elsevier Ltd. All rights reserved.