Grain development is one of the biological processes, which contributes to the final grain yield. To understand the molecular changes taking place during the early grain development, we profiled proteomes of two common wheat cultivars P271 and Chinese Spring (CS) with large and small grains, respectively at three grain developmental stages (4, 8, and 12 days post anthesis). An iTRAQ (isobaric tags for relative and absolute quantitation) based proteomics approach was used for this purpose. More than 3,600 proteins were reported to accumulate during early grain development in both wheat cultivars. Of these 3,600 proteins, 130 expressed differentially between two wheat cultivars, and 306 exhibited developmental stage-specific accumulation in either or both genotypes. Detailed bioinformatic analyses of differentially expressed proteins (DEPs) from the large- and small-grain wheat cultivars underscored the developmental differences observed between them and shed light on the molecular and cellular processes contributing to these differences. In silico localization of either or both sets of DEPs to wheat chromosomes exhibited a biased genomic distribution with chromosome 4D contributing largely to it. These results corresponded well with the earlier studies, performed in common wheat, where chromosome 4D was reported to harbor QTLs for yield contributing traits specifically grain length. Collectively, our results provide insight into the molecular processes taking place during early grain development, a knowledge, which may prove useful in improving wheat grain yield in the future.