Recent genomic and functional genomics analyses have substantially improved the understanding on gluten proteins, which are important determinants of wheat grain quality traits. The new insights obtained and the availability of precise, versatile and high-throughput genome editing technologies will accelerate simultaneous improvement of wheat end-use and health-related traits. Being a major staple food crop in the world, wheat provides an indispensable source of dietary energy and nutrients to the human population. As worldwide population grows and living standards rise in both developed and developing countries, the demand for wheat with high quality attributes increases globally. However, efficient breeding of high-quality wheat depends on critically the knowledge on gluten proteins, which mainly include several families of prolamin proteins specifically accumulated in the endospermic tissues of grains. Although gluten proteins have been studied for many decades, efficient manipulation of these proteins for simultaneous enhancement of end-use and health-related traits has been difficult because of high complexities in their expression, function and genetic variation. However, recent genomic and functional genomics analyses have substantially improved the understanding on gluten proteins. Therefore, the main objective of this review is to summarize the genomic and functional genomics information obtained in the last 10 years on gluten protein chromosome loci and genes and the cis- and trans-factors regulating their expression in the grains, as well as the efforts in elucidating the involvement of gluten proteins in several wheat sensitivities affecting genetically susceptible human individuals. The new insights gathered, plus the availability of precise, versatile and high-throughput genome editing technologies, promise to speed up the concurrent improvement of wheat end-use and health-related traits and the development of high-quality cultivars for different consumption needs.