The thymus is a central hematopoietic organ which produces mature T lymphocytes with diverse antigen specificity. During development, the thymus primordium is derived from the third pharyngeal endodermal pouch, and then differentiates into cortical and medullary thymic epithelial cells (TECs). TECs represent the primary functional cell type that forms the unique thymic epithelial microenvironment which is essential for intrathymic T-cell development, including positive selection, negative selection and emigration out of the thymus. Our understanding of thymopoiesis has been greatly advanced by using several important animal models. This review will describe progress on the molecular mechanisms involved in thymus and T cell development with particular focus on the signaling and transcription factors involved in this process in mouse and zebrafish.