The invasive procedures amniocentesis and chorionic villus sampling (CVS) are routinely applied in pregnancies at risk for fetal abnormalities and the results obtained are the gold standard for prenatal diagnosis. Because these methods of fetal cell procurement involve a 0.5-2% risk for fetal loss, they are recommended mainly in cases at high risk for fetal genetic or cytogenetic abnormalities. The development of a reproducible, reliable, noninvasive method based on retrieval of rare fetal cells from the maternal circulation will render testing feasible for the general population. Despite intensive investigation, a satisfactory, clinically acceptable method has not yet emerged. Several cell types have been targeted to this end, mostly nucleated red blood cells (NRBC), CD34+ hematopoietic progenitors, and trophoblasts. Although these cell types have been unequivocally proven to be present in the maternal circulation, each bears a significant disadvantage, rendering their application in clinical testing currently impossible: NRBC cannot be expanded in culture, thereby ruling out metaphase chromosome analysis, an essential component of prenatal diagnosis. CD34+ cells do posses the potential for in vitro proliferation, however, they have been found to persist in the maternal circulation after delivery, thereby complicating diagnosis in consecutive pregnancies. Trophoblasts are not consistently detected in the maternal circulation. Moreover, due to the lack of a definitive fetal cell marker and a reliable sorting method, foolproof fetal cell identification of any of these cell types is not possible. This report outlines the obstacles that impede development of a method for noninvasive fetal cell sampling for prenatal genetic diagnosis, along with a description of our efforts to analyze simultaneously two fetal blood cell types, NRBC and CD34+ cells in maternal blood during pregnancy, and the problems encountered. This work and that of others lead us to suggest potential future directions to help develop this important technique.