The discovery of cell-free circulating fetal nucleic acids in maternal plasma has opened up new possibilities in non-invasive prenatal diagnosis. The rapid advancement of this field in the past decade is catalysed by the discovery of new classes of fetal nucleic acid markers and technological developments in nucleic acid detection and amplification. In this review, some of the more significant recent developments in this field will be discussed, including the detection of single molecule, chromosomal aneuploidies, single nucleotide variations and placental microRNAs in maternal plasma.