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Current screening for fetal aneuploidies relies on biochemical and ultrasound measurements, and the sensitivity and specificity needs to be improved to reduce the number of pregnant women subjected to invasive diagnostic procedures, such as amniocentesis. Proteomic technologies enable new strategies for discovering biomarkers from complex biological fluids in a high-throughput and sensitive manner. Since mass spectrometry-based techniques allow for both qualitative and quantitative analysis of a given proteome, they have been widely used to resolve and compare the proteome of maternal plasma, serum, urine, cervical-vaginal fluid, and amniotic fluid. Comparisons of proteomes of normal fluids with those from aneuploidy pregnancies have revealed a host of candidate markers that still need to be verified. In parallel with proteomics, there is interest in other emerging techniques, such as RNA-SNP analysis or quantitation of fetal DNA by shotgun sequencing. Although these genomic techniques hold much promise, discovery of additional markers via quantitative proteomic comparisons could drastically improve current conventional screening at reasonable cost. Proteomics-based biomarker discovery is applicable to detection of not just aneuploidies, but also other pregnancy-related diseases.