Background: Down syndrome (DS) is the most common genetic cause of intellectual disability. Prior research has primarily focused on associated medical problems and skill deficits. This study takes a novel positive psychology approach by examining critical individual characteristics and environmental factors that facilitate exceptional quality of life for people with DS. Method: A qualitative multiple case study design was used to document the lives of four adults thriving with DS. Thriving was defined as high subjective well-being coupled with continued personal development. Results: Descriptive contexts were provided for each case along with four overarching themes: a supportive social ecology, high expectations for independence, advocacy, and strengths facilitating happiness. A new conceptual framework for understanding thriving with DS was proposed. Conclusions: These findings provide insight as to what is possible for people with DS, including ideas for future research and practice to promote thriving in the DS population.