The accelerating pace of gene discovery, coupled with novel plant breeding technologies, provides tangible opportunities with which to engineer disease resistance into agricultural and horticultural crops. This is especially the case for potato, wheat, apple and banana, which are afflicted with fungal and bacterial diseases that impact significantly on each crop's economic viability. Yet public scepticism and burdensome regulatory systems remain the two primary obstacles preventing the translation of research discoveries into cultivars of agronomic value. In this perspective review, the potential to address these issues is explained, and specific opportunities arising from recent genomics-based initiatives are highlighted as clear examples of what can be achieved in respect of developing disease resistance in crop species. There is an urgent need to tackle the challenge of agrichemical dependency in current crop production systems, and, while engineering for disease resistance is possible, it is not the sole solution and should not be proclaimed as so. Instead, all systems must be given due consideration, with none dismissed in the absence of science-based support, thereby ensuring that future cropping systems have the necessary advantage over those pathogens that continue to inflict losses year after year.