This introductive chapter presents the most important disruptions of concepts concerning the thymus since its discovery in Antique Greece. For centuries, the thymus was considered as a vestigial organ, and its role in T-cell differentiation was proposed only in the 1960s. Most recent studies attribute to the thymus an essential and unique role in programming central immunological self-tolerance. The basic mechanism implicated in this function is the transcription in the thymic epithelium of genes encoding precursors of neuroendocrine-related and tissue-restricted self-peptides. Their processing leads to the presentation of self-antigens by the major histocompatibility complex (MHC) machinery expressed by thymic epithelial and dendritic cells. Already during foetal life, this presentation promotes negative selection of T lymphocytes harbouring a receptor with high affinity for MHC/self-peptide complexes. Mainly after birth, this presentation also drives the generation of regulatory T cells specific for these complexes. Numerous studies, as well as the identification of Aire and Fezf2 genes, have shown that a thymus defect plays a crucial role in the development of autoimmunity. The discovery of the central tolerogenic action of the thymus revolutionized the whole field of immunology, and such knowledge will pave the way for innovative tolerogenic therapies against autoimmunity, the so heavy tribute paid by mankind for the extreme diversity and efficiency of adaptive immunity.