Gluten proteins (gliadins and glutenins) comprise nearly 80% of the total protein of wheat grain and account for the specific visco-elastic properties of dough. They, along with other groups of less abundant grain proteins such as puroindolines determining endosperm texture, α-amylase/trypsin inhibitors (ATI), farinins, purinins, and non-specific lipid transfer proteins, are attributed to the prolamin superfamily. Gluten proteins, mainly gliadins, puroindolines, and ATIs, became CRISPR/Cas9 editing targets for wheat improvement via knockout of respective genes. Prolamins can cause multiple diseases, of which the most important are celiac disease, wheat allergy, and nonceliac gluten sensitivity in predisposed patients. The immunotoxicity of prolamins is due to specific conservative amino acid motifs. Different approaches can be used to reduce immunotoxicity and thus provide people with sensitivity to particular groups of prolamins with safe food products. The traditional way to obtain wheat with reduced immunotoxicity is to select genotypes with null alleles at certain prolamin loci resulting from spontaneous or induced mutagenesis. Another approach is genetic modification (GM) for silencing prolamin genes by RNA interference. The most precise, flexible, and modern approach is gene editing by CRISPR/Cas techniques, which allows targeted knockout of certain groups of prolamin genes or even single genes. All three approaches provided wheat genotypes with reduced immunotoxicity. Still, CRISPR/Cas editing is the most effective approach for decreasing wheat immunotoxicity, as it produces non-GM genotypes with only targeted mutations, without undesirable mutations in other genomic regions. CRISPR/Cas9 techniques were effectively employed to reduce the contents of different groups of prolamins, mostly gliadins, and thus decrease the immunotoxic properties of wheat products. In most cases, the reduction in gliadin content was associated with an increase in bread-making quality indices due to greater accumulation of glutenins. Genotypes with targeted ATI genes are promising for developing wheat cultivars with reduced allergenicity. Products from gene-edited wheat could also be considered safer prophylaxis foods for people without pronounced symptoms of wheat-induced disorders.