The thymus is the primary lymphoid organ in which the T cell repertoire is generated. The complex cellularity of this organ is uniquely designed to facilitate T cell development: defects in thymus development or function can cause immunodeficiencies ranging from the absence of T cell-mediated immunity to broad-spectrum autoimmune disease. Peak thymus size and output occurs early in life, after which the thymus undergoes a natural process of involution. This results in the progressive loss of functional thymus tissue and correspondingly in decreased production of new naïve T cells with age - contributing to the diminished capacity of the aged immune system to adequately respond to new antigenic challenge. Age-related thymic involutions, together with the thymic involutions associated with cytotoxic therapies (e.g., radio- or chemotherapy), have raised interest in development of clinically useful protocols for boosting thymus function in vivo, by reactivating or protecting the endogenous thymus or via thymus transplantation. Improvements in this area are likely to depend on an intimate understanding of the mechanisms regulating development and maintenance of the thymus, and in particular of its stromal components. We here review current understanding of these mechanisms, focusing specifically on the epithelial component of the thymic stroma since this highly specialized lineage directs thymus development and is required critically to mediate many of the organ's specialist functions.