The past few years have witnessed considerable advances in our understanding of the mechanisms underlying the induction of central tolerance. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by virtue of promiscuous expression of tissue‐restricted autoantigens. This brief review covers progress of the last two years in deciphering the functional interrelationship among TEC development, promiscuous gene expression, and central tolerance. We discuss new insights into signaling pathways directing the differentiation and homeostasis of mTECs, and new clues to the molecular regulation of promiscuous gene expression (pGE), including the role of the transcriptional regulator autoimmune regulator (AIRE). Furthermore, we emphasize the importance of promiscuous expression of particular tissue‐restricted self‐antigens in preventing organ‐specific autoimmunity and evaluate new data supporting the threshold model of central tolerance.