The Fusarium species Fusarium graminearum and Fusarium culmorum, which are responsible for Fusarium head blight (FHB) disease, reduce world-wide cereal crop yield and, as a consequence of their mycotoxin production in cereal grain, impact on both human and animal health. Their study is greatly promoted by the availability of the genomic sequence of F. graminearum and transcriptomic resources for both F. graminearum and its cereal hosts. Functional genomic, proteomic and metabolomic studies, in combination with targeted mutagenesis or transgenic studies, are unravelling the complex mechanisms involved in Fusarium infection, penetration and colonization of host tissues, and host avoidance thereof. This review illuminates and integrates emerging knowledge regarding the molecular crosstalk between Fusarium and its small-grain cereal hosts. An understanding of the complexity of the host-pathogen interactions will be instrumental in designing new efficient strategies for the control of FHB disease.