Esophageal allergic responses to food antigens are driven by barrier impairment. Decreases in the esophageal levels of the serine protease SPINK7 lead to increased serine protease activity, which impairs epithelial barrier function and in turn causes innate epithelial proinflammatory responses, including TSLP production. TSLP promotes Th2 responses. This reaction can be controlled by anti-TSLP, anti–IL-13, and/or anti–IL-4R antibodies. In addition, loss of SPINK7 promotes increased esophageal uPA activity that activates eosinophils. Antiprotease replacement of SPINK7, such as A1AT delivery, could potentially restore these pathways. Increased IL-13 promotes epithelial cells to produce eotaxin-3 that attracts eosinophils to the esophagus. Anti–IL-5, anti–IL-5R, and anti–Siglec-8 therapy reduce and/or eliminate eosinophils. IL-13 also induces decreased expression of the desmosomal protein DSG1, thereby impairing the epithelial barrier, as well as increased expression of the cysteine protease CAPN14, which also impairs the epithelial barrier. Therapeutic reagents that are FDA approved or in clinical trials are shown in red and blue, respectively.