Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Individuals with Ds demonstrate cognitive deficits in addition to comorbidities including cardiac defects, pulmonary arterial hypertension (PAH), low blood pressure (BP), and differences in autonomic regulation. Many individuals with Ds are born with heart malformations and some can be surgically corrected. Lower BP at rest and in response to exercise and other stressors are a prevalent feature in Ds. These reduced cardiovascular responses may be due to underlying autonomic dysfunction and have been implicated in lower exercise/work capacity in Ds, which is an important correlate of morbidity, mortality and quality of life. Exercise therapy can be beneficial to normalize autonomic function and may help prevent the development of co-morbidities in Ds. We will review cardiovascular physiology and pathophysiology in individuals with Ds, along with exercise therapy and special considerations for these individuals.