Eosinophilic esophagitis (EoE) is an emerging disease that is distinguished from gastroesophageal reflux disease (GERD) by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming factor beta (TGF-β) production and signaling, to EoE pathophysiology.