The spleen has long been considered a dispensable organ. Recent research, however, has found that the spleen of adult mice holds a reservoir of stem cells that can rapidly and robustly differentiate into functional cells of diverse lineages. Splenic stem cells express Hox11, a key embryonic transcription factor that regulates organogenesis. The presence of multi-lineage stem cells in the spleen might represent lifelong persistence of cells from a primitive embryonic region called the aorta-gonad-mesonephros. By bringing together findings from diverse disciplines, we propose that the adult spleen is an important source of multi-lineage stem cells for future cellular therapies for diabetes and other diseases.