Omenn syndrome (OS) is a peculiar immunodeficiency in which profound T and B cell defects are associated with severe autoimmune manifestations. Although the molecular and biochemical bases of OS have been elucidated, the mechanisms leading to T cell infiltration of peripheral tissues such as skin and gut still remain unsolved. Two murine models with hypomorphic mutations in rag genes reproducing OS features and a murine model of lymphopenia-derived autoimmunity with similar immunopathology were recently described. The aim of this review is to integrate clues regarding the roles of impaired thymic development and lymphopenia into the pathogenesis of autoimmunity.