Down syndrome (DS) is a neurodevelopmental disorder caused by trisomy of chromosome 21. DS confers the impacted individual an elevated risk of developing various conditions of multiple organ systems. We discuss the topic of regression in individuals with DS, which has been a subject of growing attention in the past two decades, especially for onset in late adolescence to young adulthood. We share the stories of three young individuals with DS who developed regression to demonstrate the heterogeneity of etiology, treatment response, and prognosis. The importance of taking a time-sensitive and multi-disciplinary approach in evaluating and treating regressed individuals with DS cannot be overstated.