A comprehensive single-cell RNA-seq atlas of the human esophagus reveals dynamic cellular changes in eosinophilic esophagitis (EoE) and remission. The study analyzed 421,312 cells from 7 healthy and 15 EoE patients, identifying 60 distinct cell subsets, including epithelial, stromal, myeloid, and lymphoid cells. Active EoE is characterized by increased ALOX15⁺ macrophages, PRDM16⁺ dendritic cells, and cycling mast cells, alongside reduced T_H17 cells. EoE-associated genes such as NOVA1 and ATP10A are expressed in fibroblasts and PRDM16⁺ DCs, respectively. In remission, cell compositions largely restore to healthy levels, with some persistent changes, including reduced CD4⁺ resident memory T cells. EoE is driven by type 2 cytokine-driven inflammation, involving interactions between immune, epithelial, and stromal cells. Active EoE shows increased expression of IL-9⁺ IL-4⁺ IL-13⁺ T_H2 cells and endothelial cells, which interact with mast cells. Mast cells and eosinophils are recruited via IL-9 and eotaxins, with fibroblasts playing a key role in fibrostenotic complications. In remission, inflammation-associated signatures, such as mast cell and CD4⁺ T_RM cell contraction, are resolved. Rare resident ILC2s in EoE express IL-13, IL-5, and prostaglandins, contributing to inflammation. T_H17 cells decrease in active EoE, while T_H2 cells increase. Interferon-γ response signatures are correlated across cell types, with IFNG⁺ CD8⁺ T cells influencing gene expression in other T cell subsets. Plasma B cells, particularly IgG⁺ and IgM⁺ cells, increase in active EoE, highlighting their role in immune responses. EoE risk genes, including those associated with Mendelian diseases, are expressed in specific cell types, such as apical cells, fibroblasts, and mast cells. These genes form modules based on cell type-specific expression and co-expression, providing insights into EoE pathogenesis. The study underscores the importance of cell-cell interactions in maintaining tissue homeostasis and highlights therapeutic opportunities beyond eosinophil depletion. The atlas serves as a reference for understanding EoE and other esophageal diseases.A comprehensive single-cell RNA-seq atlas of the human esophagus reveals dynamic cellular changes in eosinophilic esophagitis (EoE) and remission. The study analyzed 421,312 cells from 7 healthy and 15 EoE patients, identifying 60 distinct cell subsets, including epithelial, stromal, myeloid, and lymphoid cells. Active EoE is characterized by increased ALOX15⁺ macrophages, PRDM16⁺ dendritic cells, and cycling mast cells, alongside reduced T_H17 cells. EoE-associated genes such as NOVA1 and ATP10A are expressed in fibroblasts and PRDM16⁺ DCs, respectively. In remission, cell compositions largely restore to healthy levels, with some persistent changes, including reduced CD4⁺ resident memory T cells. EoE is driven by type 2 cytokine-driven inflammation, involving interactions between immune, epithelial, and stromal cells. Active EoE shows increased expression of IL-9⁺ IL-4⁺ IL-13⁺ T_H2 cells and endothelial cells, which interact with mast cells. Mast cells and eosinophils are recruited via IL-9 and eotaxins, with fibroblasts playing a key role in fibrostenotic complications. In remission, inflammation-associated signatures, such as mast cell and CD4⁺ T_RM cell contraction, are resolved. Rare resident ILC2s in EoE express IL-13, IL-5, and prostaglandins, contributing to inflammation. T_H17 cells decrease in active EoE, while T_H2 cells increase. Interferon-γ response signatures are correlated across cell types, with IFNG⁺ CD8⁺ T cells influencing gene expression in other T cell subsets. Plasma B cells, particularly IgG⁺ and IgM⁺ cells, increase in active EoE, highlighting their role in immune responses. EoE risk genes, including those associated with Mendelian diseases, are expressed in specific cell types, such as apical cells, fibroblasts, and mast cells. These genes form modules based on cell type-specific expression and co-expression, providing insights into EoE pathogenesis. The study underscores the importance of cell-cell interactions in maintaining tissue homeostasis and highlights therapeutic opportunities beyond eosinophil depletion. The atlas serves as a reference for understanding EoE and other esophageal diseases.