This article reviews the general health care guidelines pertaining to pediatric patients with Down syndrome and presents, in a systems-based approach, an update of the current evidence behind these guidelines. To ensure the best possible long-term outcome for these patients, clinicians should provide routine well-child examinations and immunizations while maintaining a high index of suspicion for comorbid conditions more common in Down syndrome. The primary care provider should be prepared to provide information on community resources, to coordinate care with subspecialists, and to refer to early intervention services as soon as the diagnosis is made.