Due to improvements in recognition and management of their multisystem disease, the long-term survival of infants, children, and adolescents with trisomy 21 and congenital heart disease now matches children with congenital heart disease and no genetic condition in many scenarios. Although this improved survival is a triumph, individuals with trisomy 21 and congenital heart disease have unique and complex care needs in the domains of physical, developmental, and psychosocial health, which affect functional status and quality of life. Pulmonary hypertension and single ventricle heart disease are 2 known cardiovascular conditions that reduce life expectancy in individuals with trisomy 21. Multisystem involvement with respiratory, endocrine, gastrointestinal, hematological, neurological, and sensory systems can interact with cardiovascular health concerns to amplify adverse effects. Neurodevelopmental, psychological, and functional challenges can also affect quality of life. A highly coordinated interdisciplinary care team model, or medical home, can help address these complex and interactive conditions from infancy through the transition to adult care settings. The purpose of this Scientific Statement is to identify ongoing cardiovascular and multisystem, developmental, and psychosocial health concerns for children with trisomy 21 and congenital heart disease from birth through adolescence and to provide a framework for monitoring and management to optimize quality of life and functional status.