The Brisighella Heart Study (BHS) is a long-term, prospective, population-based longitudinal study on 2939 randomly selected residents of the town of Brisighella, in Emilia-Romagna, Italy. Upon enrollment in 1972, no participant had any cardiovascular disease, 1491 participants were men and 1448 women, and the age span was 14 to 84 years. The observational phase of the study contributed to the evidence of a strong pathophysiological association between hypercholesterolemia and hypertension. The interventional phase was one of the first examples of successful cardiovascular risk reduction obtained through a population-based educational intervention. Currently, the BHS staff is planning its 11th four-yearly population survey in 2022. Today, the study is moving from an epidemiological perspective to a translational approach, involving advanced biomolecular analyses, genetic tests, and functional vascular investigations. This review aims to summarize the main findings of the first 50 years of BHS research and spot the latest developments and future perspectives of this remarkable Italian cardiovascular study.