The article provides a historical overview of the search for genetic variants influencing susceptibility to chronic diseases, from R.A. Fisher's early work to the current focus on whole-genome association studies (WGAS). It discusses the concepts behind identifying common and rare variants as disease causal factors. The identification of rare variants involves careful selection of candidate genes, efficient resequencing techniques, and assessment of functional consequences. The authors argue that this strategy can help unravel the contribution of rare variants to multifactorial inheritance of common diseases, potentially leading to preventive screening schemes. The historical background includes studies on ABO blood groups and disease associations, HLA types and disease associations, and the rare variant hypothesis in colorectal cancer. The rare variant hypothesis suggests that a significant proportion of inherited susceptibility to common diseases may be due to low-frequency variants affecting disease risk. The article compares the frequencies and functional implications of common and rare variants, highlighting that rare variants often have higher odds ratios (ORs) and penetrances, making them more suitable for preventative strategies. The search for common variants relies on large-scale genotyping, while rare variants require extensive resequencing of candidate genes. Both types of variants have low penetrances, making family studies less relevant for their discovery and analysis. The article concludes that while WGAS have uncovered many polymorphic variants, the practical applications of these findings in disease understanding and prevention are limited due to small ORs. In contrast, rare variants may have substantial contributions to multifactorial inheritance and could justify preventative screening strategies. The authors emphasize the need for advanced DNA sequencing technologies to identify rare variants and suggest potential intersections between studies of common and rare variants.The article provides a historical overview of the search for genetic variants influencing susceptibility to chronic diseases, from R.A. Fisher's early work to the current focus on whole-genome association studies (WGAS). It discusses the concepts behind identifying common and rare variants as disease causal factors. The identification of rare variants involves careful selection of candidate genes, efficient resequencing techniques, and assessment of functional consequences. The authors argue that this strategy can help unravel the contribution of rare variants to multifactorial inheritance of common diseases, potentially leading to preventive screening schemes. The historical background includes studies on ABO blood groups and disease associations, HLA types and disease associations, and the rare variant hypothesis in colorectal cancer. The rare variant hypothesis suggests that a significant proportion of inherited susceptibility to common diseases may be due to low-frequency variants affecting disease risk. The article compares the frequencies and functional implications of common and rare variants, highlighting that rare variants often have higher odds ratios (ORs) and penetrances, making them more suitable for preventative strategies. The search for common variants relies on large-scale genotyping, while rare variants require extensive resequencing of candidate genes. Both types of variants have low penetrances, making family studies less relevant for their discovery and analysis. The article concludes that while WGAS have uncovered many polymorphic variants, the practical applications of these findings in disease understanding and prevention are limited due to small ORs. In contrast, rare variants may have substantial contributions to multifactorial inheritance and could justify preventative screening strategies. The authors emphasize the need for advanced DNA sequencing technologies to identify rare variants and suggest potential intersections between studies of common and rare variants.