Fusarium head blight (FHB) is one of the most devastating diseases of wheat (Triticum aestivum), barley (Hordeum vulgare) and other small grain cereals grown in warm and humid regions worldwide. In addition to yield loss, the disease compromises the quality of infected grain as a result of contamination with a range of Fusarium mycotoxins that are harmful to human and animal health. Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin found in Fusarium-infected grains. DON acts as a virulence factor for Fusarium, facilitating disease spread within wheat heads. Resistance to DON is an innate component of FHB resistance. Here we review FHB as a globally important disease, with a specific focus on the role of DON in disease development, the importance of its' resistance in plant defence against Fusarium and the current knowledge regarding the genes activated as part of the cereal defence against the toxin.