Prenatal diagnosis is to make the diagnosis of fetal structural abnormalities, genetic diseases, and pregnancy-related diseases before birth thus could offer evidence for intrauterine treatment or selectively termination of pregnancy. Up to now, researchers have applied multi-omics, including genomics, transcriptomics, and proteomics, in the discovery of prenatal diagnostic biomarkers. They have found some candidate biomarkers for aneuploids, preeclampsia, intrauterine growth retardation, and congenital structural abnormalities. With the momentous progress of biomarkers’ identification based on multi-omics for prenatal diagnosis, noninvasive prenatal testing (NIPT) has experienced tremendous progress and is revolutionizing prenatal screening and diagnosis over the past few decades. Extensive studies have also demonstrated the value of biomarkers. In particular, cell-free DNA (cfDNA), allows for a definitive diagnosis in early pregnancy for fetal diseases, including Down syndrome and other common aneuploidies. The cfDNA can be extracted from maternal plasma, posing no risk of miscarriage compared to the traditional invasive diagnosis directly analyzing fetal cells from amniocentesis or chorionic villus sampling. In this review, we would discuss the main advances, strengths, and limitations in the application of biomarkers for prenatal diagnosis along with the analysis of several representative fetal diseases.