Abstract: Zinc and selenium are two essential trace elements for human, insufficient intake can cause some health problems in the human body. Wheat are important source of zinc and selenium for a large population of northern China, however, the main wheat production areas are located in calcareous soils with zinc and selenium deficiency or potential deficiency, resulting in relatively low Zn and Se contents in wheat grains and malnutrition of Zn and Se more often happened in people of the region. This paper reviews the agronomic biofortification measures of Zn and Se in wheat grains, the distribution of Zn and Se in grains, the existing forms and bioavailability, and the application status of biofortification measurements. Soil application alone or combined with foliar spraying of zinc fertilizer are thought reasonable measurements for wheat zinc enhancement in extremely zinc-deficient soils, while on the potentially Zn-deficient calcareous soils in northern China, foliar spraying is found more efficient. In detail, two or three foliar applications of 0.3%−0.4% ZnSO₄·7H₂O, equaling a total amount of about 2.5 kg/hm², and containing surfactants in it, at the early stage of grain filling, could achieve the general zinc enrichment goal of Zn 40−60 mg/kg in wheat grains. Zn concentration decreases from outside to inside of grains, and the content of central endosperm which is more closely related to human intake is the lowest. Therefore, more attention should be paid to the concentration and bioavailability of zinc enriched in endosperm, and the standard for zinc enrichment in endosperm should be established. Moreover, the inorganic elements in food are highly toxic, with low bioavailability and unsatisfactory absorption and utilization. However, only organic elements are more safe and effective for humans. Therefore, it is necessary to clarify whether exogenous inorganic Zn is converted into organic storage in enrichment wheat grains. Se biofortification of wheat is often achieved through soil or foliar application of selenite or selenate. As soil application is low and unstable in Se use efficiency due to the varied soil pH, organic matter, and other influence factors, foliar application is recommended. The common foliar application method is spraying 20−30 g/hm² sodium selenite or sodium selenate at the early stage of grain filling, which could achieve the general selenium enrichment goal of Se 0.25−0.30 mg/kg in wheat grains. Unlike Zn, Se is relatively evenly distributed in the grains, and the Se content in the endosperm accounts for 96.2% to 97.4% of the total Se in whole grains. At the same time, the organic Se safe for the human body accounted for more than 80% of the total Se, and different organic Se forms serve different roles on humans. Although the theoretical and technical system of spraying zinc or selenium alone on the blade surface is perfect and the practical strengthening effect is good, its economic benefits are not fully reflected, which affects the application and popularization of this technology. Recently, more researchers have committed to the combined foliar application of Zn and Se with the agronomic measures of “one spraying and three preventions” increasing, which has formed an effective connection with the actual production of wheat, and provides an application technology for wheat zinc and selenium enrichment. However, the interaction between zinc and selenium different pesticides, and various trace elements when sprayed together, and the physiological and molecular mechanisms of zinc and selenium biofortification and grain zinc and selenium storage by foliar spraying are still unclear and worthy of further discussion.