Down syndrome (trisomy 21) has many manifestations that affect multiple organ systems, and we describe the wide array of imaging findings. Common cardiovascular and gastrointestinal entities are congenital heart disease (atrioventricular canal), bowel atresias (duodenal and anal), and Hirschsprungs disease. Children with Down syndrome have an 18-20 fold increased incidence of leukemia. Pulmonary hypoplasia, lung cysts, and pig bronchus (origin of the right upper lobe bronchus from the trachea) have been described. Neurologic findings include mineralizing vasculopathy of the basal ganglia, Moyamoya disease, and cerebellar/vermian hypoplasia. Musculoskeletal manifestations are numerous and include eleven ribs, hypersegmented sternum, abnormal pelvis, joint laxity/dislocations, and DDH (developmental dysplasia of the hip). Of special importance is the "triple jeopardy" of the upper cervical spine (atlanoaxial subluxation, hypoplastic posterior arch of C1, and atlantooccipital instability) and the resulting controversial cervical spine radiographic screening of children with Down syndrome. Knowledge of the many anomalies associated with Down syndrome can aid the clinician, not only in diagnosing abnormalities in these patients, but also in counseling families for potential problems that can occur in these children.