ABSTRACT: Biofortification breeding for three important micronutrients for human health, namely, iron (Fe), zinc (Zn), and provitamin A (PVA), has gained momentum in recent years. HarvestPlus, along with its global consortium partners, enhances Fe, Zn, and PVA in staple crops. The strategic and applied research by HarvestPlus is driven by product-based impact pathway that integrates crop breeding, nutrition research, impact assessment, advocacy, and communication to implement country-specific crop delivery plans. Targeted breeding has resulted in 393 biofortified crop varieties by the end of 2020, which have been released or are in testing in 63 countries, potentially benefitting more than 48 million people. Nevertheless, to reach more than a billion people by 2030, future breeding lines that are being distributed by Consultative Group on International Agricultural Research (CGIAR) centers and submitted by National Agricultural Research System (NARS) to varietal release committees should be biofortified. It is envisaged that the mainstreaming of biofortification traits will be driven by high-throughput micronutrient phenotyping, genomic selection coupled with speed breeding for accelerating genetic gains. It is noteworthy that targeted breeding gradually leads to mainstreaming, as the latter capitalizes on the progress made in the former. Efficacy studies have revealed the nutritional significance of Fe, Zn, and PVA biofortified varieties over non-biofortified ones. Mainstreaming will ensure the integration of biofortified traits into competitive varieties and hybrids developed by private and public sectors. The mainstreaming strategy has just been initiated in select CGIAR centers, namely, International Maize and Wheat Improvement Center (CIMMYT), International Rice Research Institute (IRRI), International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), International Institute of Tropical Agriculture (IITA), and International Center for Tropical Agriculture (CIAT). This review will present the key successes of targeted breeding and its relevance to the mainstreaming approaches to achieve scaling of biofortification to billions sustainably.