Biochemical prenatal screening was initiated with the use of maternal serum alpha fetoprotein to screen for open neural tube defects. Screening now includes multiple marker and sequential screening protocols involving serum and ultrasound markers to screen for aneuploidy. Recently cell-free DNA screening for aneuploidy has been initiated, but does not screen for neural tube defects. Although ultrasound is highly effective in identifying neural tube defects in high-risk populations, in decentralized health systems maternal serum screening still plays a significant role. Abnormal maternal serum alpha fetoprotein alone or in combination with other markers may indicate adverse pregnancy outcome in the absence of open neural tube defects.