The Bruneck Study is a prospective community-based study enrolling an age- and sex-stratified random sample of 1,000 men and women. It achieved an extraordinary participation rate of 93.4% and a near-complete long-term follow-up exceeding a quarter of a century (1990-2018). High-quality ascertainment of most common human diseases enables reliable evaluation of: disease epidemiology, overlaps between age-related diseases, and risk factors, and discovery of novel biomarkers. Research priorities include atherosclerosis, cardiovascular disease, aging and longevity, neurological diseases, disorders of the bone, and cancer. This review summarizes the main scientific contributions of the Bruneck Study over the past decades, outlines recent highlights, and gives an outlook of what is planned next.