Iron and zinc are 2 important nutrients in the human diet. Their deficiencies in humans lead to a variety of health-related problems. Iron and zinc biofortification of cereals is considered a cost-effective solution to overcome the malnutrition of these minerals. Biofortification aims at either increasing accumulation of these minerals in edible parts, endosperm, or to increase their bioavailability. Iron and zinc fertilization management positively influence their accumulation in cereal grains. Regarding genetic strategies, quantitative genetic studies show the existence of ample variation for iron and zinc accumulation as well as inhibitors or promoters of their bioavailability in cereal grains. However, the genes underlying this variation have rarely been identified and never used in breeding programs. Genetically modified cereals developed by modulation of genes involved in iron and zinc homeostasis, or genes influencing bioavailability, have shown promising results. However, iron and zinc concentration were quantified in the whole grains during most of the studies, whereas a significant proportion of them is lost during milling. This makes it difficult to realistically assess the effectiveness of the different strategies. Moreover, modifications in the accumulation of toxic elements, like cadmium and arsenic, that are of concern for food safety are rarely determined. Trials in living organisms with iron- and zinc-biofortified cereals also remain to be undertaken. This review focuses on the common challenges and their possible solutions related to agronomic as well as genetic iron and zinc biofortification of cereals.