The existence of cell free fetal DNA, derived from apoptotic syncytiotrophoblast, in the maternal circulation has opened new possibilities of non-invasive prenatal diagnosis. Although still some technical problems exists, especially the lack of a generic positive control on the presence of fetal DNA and the aspecific amplification of background maternal DNA, non-invasive prenatal RHD typing has been successfully introduced in several laboratories, especially in Europe. The diagnostic accuracy reaches>99%. In the Netherlands PCR guided administration of antenatal anti-D prophylaxis is cost-effective and nearby. In this review the main characteristics and applications of cell free fetal DNA are discussed, with an emphasis on prenatal RHD genotyping.