The PROactive cohort study identifies children with a chronic disease at high risk of debilitating fatigue, decreased daily life participation, and psychosocial problems, as well as children who thrive despite the challenges of growing up with a chronic condition. This cohort is based at the Wilhelmina Children’s Hospital (WKZ) in the Netherlands and includes children with a chronic condition, as well as children with medically unexplained fatigue or pain in a broad age range (2 to 18 years). Data are collected from parents (on behalf of young children) and children themselves, as well as data from their electronic health record (EHR). The mean overall age at baseline was 11.9 years, and 57% of the participants were female.