A rich past of generating and configuring genetic structures in wheat (Triticum aestivum) combined with advances in DNA sequencing, bioinformatics and genome engineering has transformed the field of wheat functional genomics. Cloning a gene from the large and complex wheat genome is no longer unattainable; in the past 5 years alone, the molecular identity of 33 wheat disease resistance genes has been elucidated. The next 15 years will see the cloning of most of the ∼460 known wheat resistance genes and their corresponding effectors. Coupled with mechanistic insights into how resistance genes, effectors and pathogenicity targets interact and are affected by different genetic backgrounds, this will drive systems biology and synthetic engineering studies towards the alluring goal of generating durable disease resistance in wheat.