Down syndrome screening has been offered to pregnant women since the early 1980s. Protocols have changed as research confirmed improvements that result in higher detection rates and lower false-positive rates. Results from 2 clinical trials evaluating screening protocols that include ultrasound measurement of nuchal translucency and biochemical testing in the first and second trimester are now available. First-trimester screening is an option if there are adequate ultrasound, diagnostic, and counseling services available. Regional variation in the availability of these services may limit the implementation of first-trimester screening. Combining screening tests for Down syndrome from both trimesters as an integrated test offers the highest detection rate with the lowest false-positive rate. The possibility of avoiding a positive screen will make this an attractive option for some. Timing, detection rate, false-positive rates, and personal factors influence the decision women make regarding screening versus diagnostic testing. This article reviews the efficacy of current protocols for Down syndrome screening. Accurate information about available screening tests will facilitate informed decisions about screening and testing.