This chapter describes the genetics. Down syndrome (DS) is the most common cause of intellectual disability with an incidence of about 1 in 800 live births. It is primarily caused by a chromosomal abnormality—trisomy of chromosome 21, which gives rise to multiple systemic manifestations as a part of the syndrome. The clinical diagnosis of trisomy 21 should be confirmed with cytogenetic studies. Karyotyping is essential to determine the risk of recurrence. The major advance in the area of prenatal screening is noninvasive testing which will avoid necessity for invasive testing like amniocentesis. Among high-risk pregnancies clinically indicated for invasive prenatal diagnosis, noninvasive detection of fetal trisomy 21 can be achieved by using multiplexed, massively parallel sequencing of maternal plasma DNA or cell-free DNA.