Prenatal screening for Down syndrome (DS) is performed by risk calculation based on biochemical and biometric parameters. This way, approximately 75-85% of all DS cases can be detected. A way to improve detection rates is to search for new screening markers. Since the majority of biomarkers used in current DS screening are predominantly produced by the placenta, and the presence of an extra chromosome (as in DS) complicates placental development and function, it is plausible to assume that new potential screening markers may also originate from the placenta. Any alterations in these markers can be attributed to abnormal placental development and function. This article focuses on normal early placental development and function compared with that in DS pregnancies. Using this knowledge, we reason towards candidate biomarkers that may be useful in screening for DS.