Down syndrome is the most prevalent genetic disorder in children, typified by pathognomonic facial stigmata, developmental delays, and variable intellectual disability. The presence of an extra chromosome 21 or its translocation to another chromosome in affected children leads to myriad multisystemic defects, anomalies, and disorders that act in synergy with their intellectual disability to impact their quality of life (QoL) negatively and shorten life expectancy. The educational attainment of these children is generally limited. However, there has been recent progress in alleviating their physical and intellectual limitations through targeted interventions. This chapter discusses the etiology of Down syndrome and its phenotypes. Also, it focuses on the current strategies that aim to improve their QoL.