The recent development of techniques to analyze foetal DNA circulating in blood maternal opened new perspectives for prenatal diagnosis (PD). Non-invasive PND (NIPD) is now the method of choice for the determination of fetal sex (genetic disorders linked to X chromosome) and rhesus genotype. NIPD begins to find applications in the diagnosis of monogenic diseases for mutations of paternal transmission. However a number of technical challenges still hamper diagnostic applications in routine, and have to be resolved taking into account the aspects of cost, reliability (false negative ..) and complexity of equipment and bioinformatics studies.