There has been a growing number of clinical case reports of regression in adolescents and adults with Down syndrome who have shown unexpected and severe regression in cognitive and adaptive functioning, motor function, communication skills, and behavior. In this chapter, we call this adult regression syndrome. It most commonly affects people with Down syndrome in their teens and twenties and is associated with cognitive-executive impairment, social withdrawal, loss of functional language and previously acquired adaptive skills, lasting greater than 3 months. The differential diagnosis is extensive suggesting that the brains of individuals with Down syndrome are vulnerable to further impairment from a variety of underlying causes. Several of the most important diagnoses are discussed further. Prognosis is highly dependent on both the cause and the certainty of the diagnosis. Further study is needed to improve our understanding of adult regression syndrome.