The article discusses the issue of "missing heritability" in complex diseases, where genome-wide association studies (GWAS) have not fully explained the genetic basis of most complex traits. Seven leading geneticists provide insights into where this heritability might lie and how it could inform research strategies. Evan E. Eichler emphasizes the need to study structural variation, such as deletions, duplications, and inversions, which are under strong selection and may contribute to disease. Jonathan Flint highlights the complexity of genetic architecture, noting that some traits are influenced by many small-effect variants, while others are affected by large-effect variants. Greg Gibson argues that GWAS may not fully capture the genetic architecture of complex traits, and that rare variants and gene-environment interactions may play a significant role. Augustine Kong discusses the importance of parental origin in genetic variants and the potential for epigenetic inheritance. Suzanne M. Leal emphasizes the role of rare variants and the need for better methods to detect associations with them. Jason H. Moore highlights the complexity of genetic interactions and the need for systems biology approaches. Joseph H. Nadeau discusses transgenerational genetic effects and the potential for epigenetic inheritance to contribute to missing heritability. The article concludes that understanding the genetic architecture of complex diseases requires a multifaceted approach, including the study of rare variants, gene-environment interactions, and epigenetic mechanisms.The article discusses the issue of "missing heritability" in complex diseases, where genome-wide association studies (GWAS) have not fully explained the genetic basis of most complex traits. Seven leading geneticists provide insights into where this heritability might lie and how it could inform research strategies. Evan E. Eichler emphasizes the need to study structural variation, such as deletions, duplications, and inversions, which are under strong selection and may contribute to disease. Jonathan Flint highlights the complexity of genetic architecture, noting that some traits are influenced by many small-effect variants, while others are affected by large-effect variants. Greg Gibson argues that GWAS may not fully capture the genetic architecture of complex traits, and that rare variants and gene-environment interactions may play a significant role. Augustine Kong discusses the importance of parental origin in genetic variants and the potential for epigenetic inheritance. Suzanne M. Leal emphasizes the role of rare variants and the need for better methods to detect associations with them. Jason H. Moore highlights the complexity of genetic interactions and the need for systems biology approaches. Joseph H. Nadeau discusses transgenerational genetic effects and the potential for epigenetic inheritance to contribute to missing heritability. The article concludes that understanding the genetic architecture of complex diseases requires a multifaceted approach, including the study of rare variants, gene-environment interactions, and epigenetic mechanisms.