All women should be offered prenatal screening or diagnostic testing for aneuploidy, regardless of maternal age, but with the increasing number of prenatal screening options now available, deciding which is the most appropriate test is increasingly complex. Nuchal translucency (NT) measurement in the first trimester is a powerful marker for Down syndrome. The combination of NT with serum markers in the first trimester detects 87% of cases of Down syndrome for a 5% false-positive rate. NT is also often increased in fetuses with a variety of other genetic conditions, including trisomies 13 and 18, Turner syndrome and triploidy, as well as structural birth defects such as congenital heart defects. Noninvasive prenatal screening using maternal cell-free DNA (cfDNA) is rapidly transforming prenatal screening, with all tests providing a high sensitivity and specificity for trisomies 21 and 18. In high-risk obstetric populations, it is recommended that this form of testing now be offered as a first-line screening option. The lower prevalence of aneuploidy in younger, low-risk women increases the false positive rate in this particular population. Additionally, trisomies 13, 18, and 21 represent a lower proportion of the chromosomal abnormalities that occur in this group compared with older women. Conventional screening methods with serum analytes and NT measurements are more likely to detect other chromosomal abnormalities, as well as the risk of other adverse pregnancy outcomes. As such, conventional screening with ultrasound (US) for NT remains the most appropriate choice for first-line screening in the general obstetric population.