Fetal cells and cell-free fetal DNA can be found circulating in maternal blood. Fetal cells recovered from maternal blood provide the only source of pure fetal DNA for noninvasive prenatal DNA diagnosis. Fetal nucleated erythrocytes (NRBCs) are considered the most suitable maternally-circulating fetal cells for this purpose, because they are not commonly found in the peripheral blood of healthy adults and are most abundant in the fetus during early gestation. Because fetal cells in maternal blood are extremely rare, a definitive separation method has not yet been established. Fetal NRBCs can be enriched from maternal blood via fluorescence- or magnetic-activated cell sorting, density gradients, immuno-magnetic beads or micromanipulation. Fetal cells are identified by Giemsa staining, hybridization with Y-chromosome specific probes, PCR-detection of a specific paternal allele, or immunostaining for fetal cell antigens. Amplification of fetal DNA sequences by primer extension preamplification and PCR has allowed prenatal screening for Duchenne muscular dystrophy and the fetal RhD blood type. Sequence-specific hybridization has been used to detect sickle cell anemia and β-thalassemia prenatally in heterozygous carriers of these disorders.The use of cell-free fetal DNA in maternal plasma for the diagnosis of single-gene disorders is limited to disorders caused by a paternally inherited gene or a mutation that can be distinguished from the maternally inherited counterpart. At present, fetal gender can be determined from maternal plasma. When a pregnant woman is a heterzygous carrier of an X-linked disorder, the determination of fetal gender is clinically very informative for first-step screening to avoid invasive amniocentesis. The non-invasive prenatal diagnosis of genetic disorders should be applied to pregnant women with a definite risk for a specific single-gene disorder.