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Wheat intolerance is a common problem for certain individuals. A gluten-free diet is the only option for people with wheat-associated disorders (WAD) to manage their condition. The elimination of immunogenic proteins from the wheat is the most appropriate approach to ameliorate the symptoms of affected individuals, while also meeting their nutritional requirements. RNA interference technology can be exploited to silence the expression of gliadins to produce a wheat variety lacking the immunogenic proteins associated with WAD, but there are challenges before implementation of transgenic varieties in the market will occur. This review is focussed on RNA interference approaches acquired to produce wheat that patients with different WAD can tolerate. The authors also discuss the advantages and disadvantages of current omics approaches that are being used to validate the food safety issues related to the applicability and clinical relevance of genetically modified wheat.