The article discusses the search for genetic variants influencing susceptibility to common diseases, contrasting common and rare variants. It traces the history from Fisher's work to modern whole-genome association studies (WGAS). Common variants are identified through large-scale studies, often with small ORs (1.2–1.5), while rare variants require careful selection of candidate genes and functional assessment. Rare variants, though less frequent, may have larger ORs and contribute significantly to disease susceptibility. The study of HLA and ABO blood groups showed early associations, but many remain unexplained. The rare variant hypothesis suggests that low-frequency variants, when combined, can have a substantial effect on disease risk. The article highlights the challenges in identifying functional effects of both common and rare variants, emphasizing the need for different strategies in their discovery. It concludes that rare variants may play a major role in multifactorial inheritance of common diseases, potentially leading to preventative screening strategies. The importance of functional assessment and the limitations of WGAS in detecting rare variants are discussed, along with the need for extensive resequencing and functional studies. The article also addresses the distinction between common and rare variants, their penetrance, and the implications for disease etiology and prevention.The article discusses the search for genetic variants influencing susceptibility to common diseases, contrasting common and rare variants. It traces the history from Fisher's work to modern whole-genome association studies (WGAS). Common variants are identified through large-scale studies, often with small ORs (1.2–1.5), while rare variants require careful selection of candidate genes and functional assessment. Rare variants, though less frequent, may have larger ORs and contribute significantly to disease susceptibility. The study of HLA and ABO blood groups showed early associations, but many remain unexplained. The rare variant hypothesis suggests that low-frequency variants, when combined, can have a substantial effect on disease risk. The article highlights the challenges in identifying functional effects of both common and rare variants, emphasizing the need for different strategies in their discovery. It concludes that rare variants may play a major role in multifactorial inheritance of common diseases, potentially leading to preventative screening strategies. The importance of functional assessment and the limitations of WGAS in detecting rare variants are discussed, along with the need for extensive resequencing and functional studies. The article also addresses the distinction between common and rare variants, their penetrance, and the implications for disease etiology and prevention.