Children with organic diseases may experience persistent pain in the presence of controlled disease, as evidenced by little or no measurable disease activity or inflammation. Historically, dualistic definitions of pain have informed standard diagnostic approaches to persistent pain; aggressive investigation and treatment targeting underlying disease, even in the absence of evidence indicating disease escalation. Evidence across disease populations, in children with inflammatory bowel disease, sickle cell disease, and juvenile idiopathic arthritis indicates that persistent pain in these conditions may be better conceptualized as functional in nature, potentially resulting from disordered somatosensory processing including central sensitization. Applying a biopsychosocial understanding of persistent pain and multidisciplinary functional pain management strategies may lead to improved health outcomes.