Molecular analysis of plasma DNA during human pregnancy has led to the discovery that maternal plasma contains both fetal and maternal DNA. This valuable source of fetal DNA opens up new possibilities for noninvasive prenatal diagnosis. Published data from the last 3 years demonstrating the feasibility and utility of analyzing fetal DNA in maternal plasma are reviewed. The detection of fetal DNA in maternal plasma is much simpler and more robust than detecting fetal nucleated cells in maternal blood, and does not require prior enrichment. This approach has been shown to have application in the prenatal diagnosis of fetal rhesus D status, sex-linked disorders, and other paternally inherited genetic disorders. Abnormal fetal DNA concentrations in maternal plasma and serum have been found in common pregnancy-associated disorders, including preterm labor and preeclampsia, as well as in pregnancies complicated by fetal trisomy 21. After delivery, fetal DNA is cleared rapidly from maternal plasma, with a half-life in the order of minutes. These clearance kinetics exhibit an important difference from fetal cell clearance, where long-term persistence has been demonstrated. It has been only 3 years since fetal DNA was first detected in maternal plasma, and much remains to be learned about the biology of this phenomenon. In addition, additional diagnostic applications beyond those discussed here can be expected in the near future.