Approximately two billion people suffer from micronutrient deficiencies worldwide and deficiencies in essential micronutrients such as Zinc (Zn) and Iron (Fe) leading to various health impairments. Biofortification strategies including genetic and agronomic approaches offers sustainable solution to improve the nutrition status of resource poor people in developing countries. The wheat biofortification breeding program at CIMMYT has made continuous progress in terms of development, distribution and deployment of Zn-enriched competitive wheat lines with increased yield potential, disease resistance and better processing quality. A decade of research and breeding efforts led to the release of several biofortified wheat varieties in target regions of South Asia and reached about 0.5 million consumers with biofortified wheat products. Breeding for high Zn concentration has been diversified with diverse crosses with progenitors from T. dicoccon based synthetics, T. spelta, T. dicoccoides, winter wheat sources, and landraces. Targeted crossing and large segregating populations led to identification of excellent transgressive segregants with high Zn and essential core traits. Eventually large number of advanced lines were grown under smaller and larger plots to identify superior lines with significantly high Zn, competitive yield potential, rust resistance and processing quality. The high-Zn wheat international trial (HPYT) distributed to more than 70 different public-private partners annually to evaluate and promote as biofortified wheat in the target regions. To accelerate breeding efficiency and mainstream grain Zn in CIMMYT wheat breeding program, several QTL regions were mapped through traditional QTL mapping and Association mapping (AM) studies. The promising and stable QTLs being validated in the new bi-parental populations and advanced breeding lines and the significant SNPs are being converted into breeder’s friendly KASP assays for efficient marker-assisted breeding. The proof-of-concept strategy of converting a SNP marker identified on chromosome 3A from ‘Kenya Swara’ background showed promising results with 7-8% increased grain Zn in a diverse CIMMYT wheat backgrounds. A rapid high-throughput screening method for grain Zn and Fe using X-ray based fluorescent technique has been utilized in CIMMYT Biofortification breeding program, in addition, a new cost-effective screening method for phyic acid content in wheat grain allows estimating Zn:PA molar ratio for increased bioavailability of Fe and Zn by reducing phytic acid levels. Integrating traditional breeding and modern genomic approaches including genomic selection strategies and high-throughput field based phenotyping techniques would accelerate development of next generation of biofortified wheat to achieve sustainable food and nutritional security in the developing world.