Fetal nucleic acids in maternal plasma have opened up new possibilities for noninvasive prenatal diagnosis of chromosomal aneuploidies. One approach is based on the measurement of the allelic ratio of single nucleotide polymorphisms in the coding region of placental mRNA. Another approach is through the analysis of DNA fragments with different patterns of DNA methylation between fetal and maternal DNA. One other alternative is to enrich the fractional concentration of fetal DNA in maternal plasma using physical or chemical methods. Finally, the development of more precise digital polymerase chain reaction-based methods for fetal nucleic acid analysis might further catalyse the developments in this area. It is hoped that plasma-based molecular prenatal diagnosis might ultimately make prenatal testing safer for pregnant women and their fetuses.