FOXN1 gene belongs to the forkhead box gene family that comprises a diverse group of "winged-helix" transcription factors that have been implicated in a variety of biochemical and cellular processes, such as development, metabolism, aging and cancer. These transcription factors share the common property of being developmentally regulated and of directing tissue-specific transcription and cell-fate decisions. Foxn1 is selectively expressed in thymic and skin epithelial cells, where it acts through its molecular targets to regulate the balance between growth and differentiation. In particular, Foxn1 is required for thymic epithelial patterning and differentiation from the initial epithelial thymic anlage to a functional cortical and medullary thymic epithelial cells (TECs) meshwork necessary for the crosstalk with the lymphoid compartment. A mutation in FoxN1 generates alymphoid cystic thymic dysgenesis due to defective TECs, causing primary T-cell immunodeficiency, named Nude/SCID syndrome, and leads to a hairless "nude" phenotype in both mice and humans. This immune defect represents the first example of a Severe Combined Immunodeficiencies (SCID) phenotype not primarily related to an abnormality intrinsic of the hematopoietic cell, but rather to a peculiar alteration of the thymic epithelia cell. This review focuses on the key role of FOXN1 in cell development and its clinical implication in humans.