For the lymphohematopoietic system, maturation-dependent alterations in DNA repair function have been demonstrated. Because little information is available on the regulatory mechanisms underlying these changes, we have correlated the expression of DNA damage response genes and the functional repair capacity of cells at distinct stages of human hematopoietic differentiation. Comparing fractions of mature (CD34-), progenitor (CD34+ 38+), and stem cells (CD34+ 38-) isolated from umbilical cord blood, we observed: 1) stringently regulated differentiation-dependent shifts in both the cellular processing of DNA lesions and the expression profiles of related genes and 2) considerable interindividual variability of DNA repair at transcriptional and functional levels. The respective repair phenotype was found to be constitutively regulated and not dominated by adaptive response to acute DNA damage. During blood cell development, the removal of DNA adducts, the resealing of repair gaps, the resistance to DNA-reactive drugs clearly increased in stem or mature compared with progenitor cells of the same individual. On the other hand, the vast majority of differentially expressed repair genes was consistently upregulated in the progenitor fraction. A positive correlation of repair function and transcript levels was found for a small number of genes such as RAD23 or ATM, which may serve as key regulators for DNA damage processing via specific pathways. These data indicate that the organism might aim to protect the small number of valuable slow dividing stem cells by extensive DNA repair, whereas fast-proliferating progenitor cells, once damaged, are rather eliminated by apoptosis.