Down syndrome, the result of trisomy of chromosome 21, is one of the most common chromosomal abnormalities. Patients have a characteristic facial appearance, variable levels of intelligence and self-care skills, and a variety of associated medical conditions. Orthopaedic manifestations occur frequently; most are related to hypotonia, joint hypermobility, and ligamentous laxity. Atlanto-occipital and atlantoaxial hypermobility, as well as bony anomalies of the cervical spine, can produce atlanto-occipital and cervical instability. Methods of screening for this instability, particularly with regard to participation in sports, are a subject of controversy. Scoliosis, hip instability, slipped capital femoral epiphysis, patellar instability, and foot deformities are other musculoskeletal conditions found in patients with Down syndrome that can be challenging for the orthopaedic surgeon to treat.