Background: Down syndrome (DS) affects ∼1 per 650–1000 live births and is the most common known genetic cause of intellectual disability. A highly significant change in the survival of people with DS has occurred during the last two generations, with life expectancy estimates increasing from 12 to nearly 60 years of age. Subjects and Methods: Detailed information on 1332 people in Western Australia with DS was abstracted from a specialist statewide database for the period 1953–2000 and electronically linked with three other state or national health and mortality data sources and the state Birth Defects Registry. Results: Over the last 25 years the percentage of women over 35 years giving birth increased from 4.8 to 18.6%, accompanied by an increase in the overall prevalence of DS from 1.1 to 2.9 per 1000 births. Four life stages of DS were identified: prenatal, childhood and early adulthood, adulthood, and senescence. Although pneumonia, or other types of respiratory infections, was the most common cause of death across the entire lifespan, ranging from 23% of deaths in adulthood to 40% in senescence, each life stage exhibited a particular profile of comorbidities. Congenital heart defects were common causes in childhood (13%) and adulthood (23%), whereas in senescence coronary artery disease (10%) and cardiac, renal, and respiratory failure (9%) were leading causes of mortality. Conclusions: A major re-appraisal in attitudes towards DS is required to ensure that the medical and social needs of people with the disorder are adequately met across their entire lifespan. In particular, specific recognition of the comorbidities that can arise at different ages is needed, accompanied by the provision of appropriate levels of care and management.