The 15 years since the discovery of fetal DNA in maternal plasma have witnessed remarkable developments in noninvasive prenatal diagnosis. An understanding of biological parameters governing this phenomenon, such as the concentration and molecular size of circulating fetal DNA, has guided its diagnostic applications. Early efforts focused on the detection of paternally inherited sequences, which were absent in the maternal genome, in maternal plasma. Recent developments in precise measurement technologies such as digital polymerase chain reaction (PCR) have allowed the detection of minute allelic imbalances in plasma and have catalyzed analysis of single-gene disorders such as the hemoglobinopathies and hemophilia. The advent of massively parallel sequencing has enabled the robust detection of fetal trisomies in maternal plasma. Recent proof-of-concept studies have detected a chromosomal translocation and a microdeletion and have deduced a genome-wide genetic map of a fetus from maternal plasma. Understanding the ethical, legal, and social aspects in light of such rapid developments is thus a priority for future research.