This article explores the various challenges systemic conditions can pose before and during orthodontic treatment. Cardiovascular conditions like infective endocarditis require antibiotic prophylaxis before certain orthodontic procedures are started. Patients with bleeding disorders require special considerations in regards to viral infection risk and maintenance of excellent atraumatic oral hygiene. Orthodontists play an important role in early identification of signs and symptoms of eating disorders and should deal with these patients sensitively. Congenital disorders, craniofacial anomalies, and nutritional deficiencies require special considerations and should be addressed appropriately before orthodontic treatment is started.