Wheat stripe rust, also known as yellow rust, is a disease caused by the fungus Puccinia striiformis f. sp. tritici (Pst) that can devastate wheat crops across the world. The most effective way to control rust diseases is by planting and breeding durable resistant wheat cultivars. The caveat of R gene-dependent disease resistance is the frequent loss of effectiveness due to pathogen mutations that allow evasion of detection by immune receptors. However, disruption of host baseline susceptibility by inactivating S genes could be adopted for broad-spectrum and durable disease resistance. A recent study finished by the research team at Northwest A&F University significantly advanced our understanding how wheat plants can be protected by a S gene and provided tools in the fight against a major disease. Upon infection, the fungus induces a receptor-like cytoplasmic kinase, TaPsIPK1, specifically interacting with the effector, PsSpg1, that promotes parasitism via enhancing kinase activity and nuclear entry of TaPsIPK1. TaPsIPK1 phosphorylates the transcription factor TaCBF1d for gene regulation. Phosphorylation of TaCBF1d switches its transcriptional activity on the downstream genes. Hence the enhanced TaCBF1d phosphorylation by TaPsIPK1 and PsSpg1 might reprogram target gene expression to disturb plant defense response and thus facilitate pathogen infection. CRISPR-Cas9 inactivation of TaPsIPK1 in wheat confers broad-spectrum resistance against Pst without impacting important agronomic traits in two-years of field tests. This is first study to reveal a new phosphorylation-transcriptional regulation mechanism triggered by PsSpg1-TaPsIPK1-TaCBF1d in wheat S genes to stripe rust, which provide a new strategy to develop cultivars with durable resistance by genetic modifications in crops.