The immune system relies on a finely tuned balance between immunity to pathogens and cancers, and tolerance to healthy self, our environment and commensals. This equilibrium is dramatically disrupted in the Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. This rare disorder is caused by mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4⁺ regulatory T (Treg) cells. IPEX usually presents in infancy, as multi-organ autoimmunity encompassing type-1-diabetes, anemia, chronic dermatitis and bowel inflammation, hepatitis and nephritis. In this review, we describe the genetic, immunological and clinical characteristics of IPEX syndrome and highlight the impact of heritable mutations on the function of Treg cells. (By Eva d’Hennezel, http://jmg.bmj.com/content/49/5/291 )