The ability to detect cell-free fetal nucleic acids in pregnant women has greatly evolved over the past decade. Dozens of papers have explored the biology, kinetics, and clinical significance of both cell-free fetal DNA and mRNA in the maternal circulation. As a result, our overall understanding of fetal nucleic acid trafficking has expanded. To date, two applications, gender determination and fetal RhD status, have translated into clinical medicine. However, with advanced molecular techniques such as mass spectrometry, real-time quantitative polymerase chain reaction, and gene expression arrays, the ease with which fetal genes can be detected within the mother has greatly improved. Newly identified placental and fetal mRNA transcripts as well as an epigenetically modified placental DNA marker, maspin, have universal applicability. Global expression analyses of fetal mRNA in both amniotic fluid and blood provide new insights into fetal development and pathology. Prenatal diagnosis is poised to evolve from detection of aneuploidy to detection of deviation from normal development, which should provide novel opportunities for fetal treatment.