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The central challenge is therefore not simply to maximize immune activation, but to identify genetic interventions that remain effective across diverse pathogen races and environmental conditions without imposing excessive penalties on growth or yield. Here, we synthesize the molecular basis of rice immunity from a design\u2010oriented perspective. We first examine cell\u2010surface pattern\u2010recognition receptors and intracellular nucleotide\u2010binding leucine\u2010rich repeat receptors, and then assess the shared signaling hubs and defence outputs that connect pathogen perception to antimicrobial responses. Rather than treating these components as equivalent breeding targets, we compare their translational potential according to resistance spectrum, anticipated durability, tunability, pleiotropic risk, and the strength of field evidence. We further discuss breeding strategies based on receptor engineering, editing of susceptibility genes and cis\u2010regulatory elements, post\u2010translational motif engineering, pathogen\u2010inducible and upstream open reading frame\u2010mediated regulation, resistance\u2010gene stacking and artificial intelligence\u2010assisted prediction. We argue that rational resistance design in rice should move beyond constitutive immune activation toward allele\u2010specific, quantitative, spatially restricted and infection\u2010responsive regulation. Integrating mechanistic insights with precision genome editing, accelerated breeding and responsible deployment offers a practical route to durable, yield\u2010compatible disease resistance while reducing dependence on chemical control.<\/jats:p>","DOI":"10.1002\/advs.77719","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:13:23Z","timestamp":1789618403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Bases and Genetic Design of Rice Disease Resistance for Optimized Yield and Sustainable Agriculture"],"prefix":"10.1002","author":[{"given":"Xinyue","family":"Hou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Rice Biology and Breeding China National Rice Research Institute  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjiang","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key 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