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ABSTRACT It is more than 40 years since the era of transgenic plants began and more than 30 years after the cloning of the first plant disease resistance genes. Despite extensive progress in our mechanistic understanding and despite considerable sustained efforts in the commercial, nonprofit, academic and governmental sectors, the prospect of commercially viable plant varieties carrying disease resistance traits endowed by biotechnological approaches remains elusive. The cost of complying with the regulations governing the release of transgenic plants is often cited as the main reason for this lack of success. While this is undeniably a substantial hurdle, other transgenic traitshavebeen successfully commercialised. We argue that a significant portion of the challenges of producing crop varieties engineered for disease resistance is intrinsic to the trait itself. In this review, we briefly discuss the main approaches used to engineer plant disease resistance. We further discuss possible reasons why they have not been successful in a commercial context and, finally, we try to derive some lessons to apply to future efforts.