Much of Yu’s research has been focused on investigating the genetic architecture of quantitative and qualitative traits with evolutionary and agricultural importance, the interplay of genes, environment, and development underlying phenotypic variation, and the strategies to enhance crop improvement by design optimization and prediction. Yu’s significant research contributions include developing the integrated framework for both gene discovery underlying phenotypic plasticity and performance prediction across environments, developing the mixed model framework for genome-wide association studies, outlining the nested association mapping strategy, pioneering genomic selection research in crops, prototyping a comprehensive strategy to turbocharge genebanks to mine the natural heritage, quantifying genic and nongenic contributions to quantitative trait variation in maize, identifying the Shattering1 gene and its homologs underlying the parallel domestication of multiple cereal species (sorghum, maize, rice, and foxtail millet), uncovering a domestication triangle involving sorghum tannin and the pair of Tannin1 and Tannin2 genes, and revealing the patterns in DNA base composition divergence and chromosome size variation across multiple species.