The human equivalent form of the severe combined congenital immunodeficiency of the nude/SCID mouse has been recently described in 2 siblings originating from a small community in southern Italy. Similar to the mouse, the human phenotype is characterized by a profound T cell ontogenetic defect associated with congenital alopecia and nail dystrophy. The disease is related in either mice and humans to molecular alterations of the gene encoding a forkhead/winged helix transcription factor, which is selectively expressed in thymic epithelia. Remarkably, due to the selectivity of the tissue expressivity of the gene responsible for the syndrome, this is the first example of SCID not primarily related to an hematopoietic cell abnormality, but rather to thymic aplasia. The opportunity to study immunological reconstitution in the absence of a functioning thymus following a bone marrow transplantation from a related HLA-identical sibling gave us insight into the role of the thymus in in vivo T cell ontogeny and maintenance of T cell functionality. This model led us to address a few general issues that may have clinical implications.