Intrathymic expression of peripheral auto-antigens, termed promiscuous gene expression, extends the scope of central T-cell tolerance to peripheral organs and proves essential for the induction and maintenance of self-tolerance. The purification of antigen-presenting cells has been instrumental in identifying promiscuous gene expression as an inherent property of medullary epithelial cells. The pool of promiscuously expressed genes might encompass up to 10% of the whole genome. The remarkable diversity of this gene pool implies a complex mode of regulation, which cannot be solely explained by the action of a single factor, such as the transcriptional autoimmune regulator AIRE. Co-localization of promiscuously expressed genes in clusters also suggests epigenetic mechanisms (e.g. DNA methylation) to account for this unorthodox gene expression pattern. The identification of the molecular components controlling the expression of tissue-restricted genes in the thymus promises to add valuable new insights into the complex genetic regulation underlying most autoimmune diseases.