Biofortification of staple food crops with micronutrients by either breeding for higher uptake efficiency or fertilization can be an effective strategy to address widespread dietary deficiency in human populations. Selenium and iodine deficiencies affect a large proportion of the population in countries targeted for biofortification of staple crops with Zn, Fe, and vitamin A, and inclusion of Se and I would be likely to enhance the success of these programs. Interactions between Se and I in the thyroid gland are well established. Moreover, Se appears to have a normalizing effect on certain nutrients in the body. For example, it increases the concentration of Zn and Fe at key sites such as erythrocytes when these elements are deficient, and reduces potentially harmful high Fe concentration in the liver during infection. An important mechanism in Se/Zn interaction is selenoenzyme regulation of Zn delivery from metallothionein to Zn enzymes. More research is needed to determine whether sufficient genetic variability exists within staple crops to enable selection for Se and I uptake efficiency. In addition, bioavailability trials with animals and humans are needed, using varying dietary concentrations of Se, I, Zn, Fe, and vitamin A to elucidate important interactions in order to optimize delivery in biofortification programs.