<p>Non-invasive prenatal screening has swiftly been implemented as a first- or second-tier test for common fetal aneuploidies and typically relies on sequencing maternal circulating cell-free DNA (cfDNA). This cfDNA comprises both the maternal and fetal genomes and the epigenetic features of its cells of origin. Here, we discuss how genetic findings beyond common fetal aneuploidies can provide important information about maternal and fetal health. Moreover, epigenetic and fragmentomic cfDNA features and cell-free RNA are emerging as powerful biomarkers of health and disease. We expound on the cfDNA and cell-free RNA analyses that have enabled first-trimester prediction of actionable pregnancy complications, such as preeclampsia, gestational diabetes, preterm birth, pregnancy-related immune-mediated disease activity and infections. This expanding scope of non-invasive prenatal screening promises to transform obstetric care from reactive to preventive, personalized medicine.</p>