Identifying and mapping grain size candidate genes in the wheat genome greatly empowers reverse genetics approaches to improve grain yield potential of wheat. Grain size (GS) or grain weight is believed to be a major driving force for further improvement of wheat yield. Although the large, polyploid genome of wheat poses an obstacle to identifying GS determinants using map-based cloning, a translational genomics approach using GS regulators identified in the model plants rice and Arabidopsis as candidate genes appears to be effective and supports a hypothesis that a conserved genetic network regulates GS in rice and wheat. In this review, we summarize the progress in the studies on GS in the model plants and wheat and identify 45 GS candidate loci in the wheat genome. In silico mapping of these GS loci in the diploid wheat and barley genomes showed (1) several gene families amplified in the wheat lineage, (2) a significant number of the GS genes located in the proximal regions surrounding the centromeres, and (3) more than half of candidate genes to be negative regulators, or their expression negatively related by microRNAs. Identifying and mapping the wheat GS gene homologs will not only facilitate candidate gene analysis, but also open the door to improving wheat yield using reverse genetics approaches by mining desired alleles in landraces and wild ancestors and to developing novel germplasm by TILLING and genome editing technologies.