High School and Beyond (HSB) began in 1980 to study how education shapes adult outcomes, and includes a nationally representative sample of 58,270 students randomly selected US public and private high schools. Data on students’ educational experiences, cognitive and non-cognitive skills, peers, educational and occupational plans, health and socioeconomic background were obtained via student, parent, school administrator and teacher questionnaires. From the initial sample of 58,270 students, a random subsample of 14,830 sophomores and 12,000 seniors were selected to participate in a longitudinal panel. A follow-up of the 25,370 surviving panelists was fielded in 2021. Questionnaires gathered information about cognitive functioning and impairment; health; work; family; finances; COVID-19; and wellbeing. Sample members completed cognitive tasks commonly employed in studies of ageing. Home health visits took anthropomorphic measures and collected saliva samples (for genomic analysis of the microbiome) and whole-blood samples (for human genomic analysis and for assaying markers of neurodegeneration).