High molecular weight glutenin subunits (HMW-GS) are the most important components in the storage protein of wheat grains. Their compositions, expressions and contents determine the dough elasticity and baking quality. This article summarized the progress of cloning, molecular characterization and functional studies of HMW-GS as well as their marker development and application in wheat breeding. Update status of different HMW-GS effects on flour processing quality, genetic transformation of several HMW-GS genes, small-scale mixograph analysis by adding prokaryotic expressed HMW-GS, and mutant developing on HMW-GS loci, were also reviewed. Besides, crucial issues in current studies on wheat HMW-GS were discussed. It is suggested that the key point on HMW-GS in the future will be to pyramid some desirable HMW-GS genes by marker assisted selection and transgenic strategies for the development of wheat varieties with good bread-making quality and the functional dissection of each HMW-GS gene accurately.