[9] In 1980, Botstein and his colleagues Ray White, Mark Skolnick, and Ronald W. Davis proposed a method[10] for constructing a genetic linkage map using restriction fragment length polymorphisms that was used in subsequent years to identify several human disease genes including Huntington's and BRCA1.

[11] This approach was refined and applied for diverse applications, including for a molecular classification of heterogenous tumors using gene expression.

These efforts included work on discovery of tumor subtypes with Lou Staudt, Ash Alizadeh and Ronald Levy, yielding a refined classification of diffuse large B cell lymphomas, and in painting the molecular portraits for refined classification of breast cancers with Anne-Lise Børresen-Dale and Charles Perou.

In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work and in 2020 the Thomas Hunt Morgan Medal of the Genetics Society of America.

[14] In 2016, Semantic Scholar AI program included Botstein on its list of most top ten most influential biomedical researchers.