Research on quality of life (QoL) of adolescents and young adults born preterm and those with congenital heart disease (CHD) was systematically reviewed, and factors associated with QoL were identified. Forty-five studies met the inclusion criteria for review. Although the majority of studies found that self-reported QoL of adolescents and young adults born preterm did not differ from term controls, several studies reported lower QoL among individuals born preterm, especially those who had additional impairments. Most studies on adolescents and young adults with CHD reported lower QoL compared with healthy peers, which may be in part due to real or perceived physical activity limitations of individuals with CHD. Overall, parents reported that their adolescents born at high risk had a less favorable QoL compared with those who served as controls. Encouraging age-appropriate, safe, and enjoyable physical activity and avoiding unnecessary restrictions and overprotection are considerations for optimizing QoL. (Contains 5 tables and 1 figure.)