One of the features of the “Great Obstetrical Syndromes” is that treatment at the time of disease is ineffective because clinical manifestations are adaptive. The long preclinical phase creates an opportunity for prediction and intervention to prevent disease. This, however, requires the development of biomarkers for early identification of women at risk. Biomarkers are measurable indicators of biological events that represent a subclinical stage or manifestation of disease. They have been used to advance the understanding of pathological processes, detect early disease, target prevention strategies and monitor treatment. Challenges for the discovery of biomarkers in perinatal medicine include the syndromic nature of obstetrical disease (multiple etiologies), low prevalence, and incomplete understanding of the mechanisms of disease. To overcome the challenges in the field, we have approached biomarker discovery using novel approaches such as i) the disaggregation of obstetrical disease by placental histopathology (divide and conquer), ii) target the search for biomarkers based on information derived from single cell genomic studies of the placenta, and iii) use crowdsourcing to involve the community and enable robust assessment of omics methods and data. Over the years, the Perinatology Research Branch has proposed biophysical and biochemical markers for several conditions, such as fetal death, acute funisitis, clinical chorioamnionitis, preeclampsia and spontaneous preterm birth, among others. This work has enabled the development of preventive strategies, such as the vaginal progesterone treatment for women with a midtrimester short cervix for reducing the rate and impact of prematurity.