Beyond natural variation: The era of rational design in plant immunity

Abstract The evolutionary arms race between crops and pathogens has reached a critical impasse: pathogen adaptation consistently outpaces the development of resistant varieties through conventional breeding. This growing imbalance highlights the need to move beyond the exclusive reliance on natural variation toward more predictive and design‐oriented approaches to crop protection. Here, we argue that rational design of immune components, which enabled by the integration of structural biology, synthetic biology, and artificial intelligence, offers a complementary path to enhance and extend plant immunity. Within this emerging framework, three strategic approaches are beginning to redefine how resistance can be engineered: (1) reprogramming pathogen recognition to counter effector evolution, (2) engineering host proteins to evade pathogen sabotage, and (3) deploying synthetic pathogen‐responsive switches to bypass growth‐defense trade‐offs. Together, these strategies shift the focus from discovering naturally occurring resistance to designing immune functions with defined properties. Although still constrained by biological complexity and implementation challenges, advances in computational protein design and genome engineering are steadily expanding the scope of what can be achieved, pointing toward a more precise and programmable paradigm of plant immunity