The spleen of human adults uniquely possesses a reservoir of multilineage adult stem cells that express the developmental transcription factor HOX11. In contrast to hematopoietic stem cells, HOX11+ stem cells hold potentially broader therapeutic applications because they are less lineage restricted. HOX11/TLX1 is part of a homeodomain gene family essential for organogenesis of the spleen and for contributions to development of hindbrain, cochlea, pancreas, salivary glands, among other organs and tissues. While HOX11/TLX1 displays widespread patterns of expression during embryogenesis, its expression was thought to cease after birth. Recent findings in human post-mortem tissue have shattered this dogma, finding that HOX11/TLX1 stem cells are uniquely and abundantly expressed throughout adulthood in the human spleen. While their role in humans is not yet understood, HOX11/TLX1 stem cells from the spleen of normal mice have been harvested to assist in both the treatment and cure at least two autoimmune diseases: type 1 diabetes, Sjogren's syndrome, and possibly their comorbid hearing loss. The splenic stem cells are infused, with an immune therapy, into diseased NOD mice, where they can home to the diseased organ, differentiate into the appropriate cell type, and assume normal functioning with the endogenous regeneration of the animal due to disease removal. This review covers HOX11/TLX1+ stem cells' success in an animal model and their potential for treating autoimmune diseases in organs that mirror their extensive expression patterns during embryogenesis.