Second trimester biomarkers were initially introduced with the intent of screening for neural tube defects and then subsequently for Down syndrome. It was soon realized that these markers can be indirect evidence of abnormal placentation and, therefore, can be used for screening for adverse pregnancy outcomes. Several new biomarkers have subsequently been described with conflicting findings regarding their efficiency for screening for adverse pregnancy outcomes. Although a biologically feasible mechanism has been proposed for the role of these biomarkers, they still fall short of an ideal screening test to be clinically useful. © 2014 John Wiley & Sons, Ltd.