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The application of recent technical developments, such as digital PCR or shot-gun sequencing, for the analysis of cell-free fetal DNA, have indicated that the long-sought goal of the noninvasive detection of Down syndrome may finally be attained. Although these methods are still cumbersome and not high throughput, they provide a paradigm shift in prenatal diagnosis, as they could effectively pronounce the end of invasive procedures, such as amniocentesis or chorionic villous sampling for the detection of such fetal anomalies. However, it remains to be determined how suitable these approaches are for the detection of more subtle fetal genetic alterations, such as those involved in hereditary Mendelian disorders (e.g., thalassemia and cystic fibrosis). New technical developments, such as microfluidics and reliable automated scanning microscopes, have indicated that it may be possible to efficiently retrieve and examine circulating fetal cells. As these contain the entire genomic complement of the fetus, future developments may include the noninvasive determination of the fetal karyotype.