Down syndrome (DS) is the most common chromosomal abnormality in humans that is compatible with life. This syndrome occurs when there is an extra copy of the 21st chromosome. Down syndrome is associated with numerous comorbidities that can pose challenges for the perioperative nurse caring for a patient with DS undergoing surgery. These challenges can affect the patient assessment, communication with the patient, and patient safety (eg, preventing complications). As the life expectancy of people with DS has increased, so too have the chances that perioperative nurses will care for a patient with this disorder. This article reviews the pathophysiology of DS, discusses common comorbidities that may directly affect perioperative care, and reviews an exemplar case study that demonstrates how personnel with knowledge of DS can positively influence surgical team decision making for these patients in the perioperative setting.