Members of the caudal (cdx) family of homeobox proteins are essential regulators of embryonic blood development in zebrafish. Previously, we reported that the murine homologues (Cdx1, Cdx2, and Cdx4) affect formation and differentiation of embryonic stem cell (ESC)-derived hematopoietic progenitor cells. Consistent with the notion that embryonic pathways can reactivate during adult oncogenesis, recent studies suggest involvement of CDX2 in human acute myeloid leukemia (AML). Here we study CDX2 in healthy and leukemic human lymphoid cells, and show that a majority of leukemic samples display various degrees of aberrant CDX2 expression. Analysis of a cohort of 37 childhood acute lymphoblastic leukemia (ALL) patients treated in our hospital reveals that high CDX2 expression levels at diagnosis correlate with persistence of minimal residual disease (MRD) during the course of treatment. Thus, CDX2 expression levels may serve as a marker for adverse prognosis in pediatric ALL.