In addition to playing an important role in the development of the central nervous system [8–11], cartilage [6,12,13], and muscle [14,15], it was shown that Sox6 is upregulated in long-term hematopoiesis stem cells (LT-HSC) compared with multipotent progenitors of adult mouse bone marrow lineage [28]. In this study, we describe that Sox6 also exerts pleiotropic effects on erythropoiesis. These effects include delayed maturation of erythrocytes (that normally enucleate prior to entering the bloodstream [27]) and higher expression of embryonic globin genes. The most extreme effect is the persistence of high expression of the embryonic ɛy globin gene. Here we describe and characterize the effects of Sox6 on the ɛy globin gene. We show that Sox6 binds to the proximal promoter of ɛy globin and represses its transcription. In wild-type (WT) mice, Sox6 is not expressed in yolk sac blood islands, but is expressed in fetal liver, the opposite expression pattern of ɛy globin. In the absence of Sox6, ɛy globin is ectopically expressed in the fetal liver, demonstrating that Sox6 functions in definitive erythropoiesis.