The allergic disorder Eosinophilic Esophagitis (EoE) is a debilitating chronic disease of the esophagus whereby substantial epithelial remodelling occurs in response to ongoing inflammation. Patients with EoE have a markedly decreased quality of life, with paediatric patients presenting with failure to thrive, and adult patients experiencing food impactions and difficulty swallowing. Despite the presence of several EoE treatments, a subset of patients remain treatment non-responsive, and no therapies currently target the epithelial defects observed in this disease. The esophageal epithelium (EE) provides a physical protective barrier to the underlying mucosa, and is maintained by epithelial cells that exhibit a proliferation/differentiation continuum. Proliferative cells of the basal layer renew the epithelium and begin the process of early differentiation in the overlying suprabasal layer, and terminally differentiate within the superficial layer. Within the esophageal epithelium, an equilibrium exists between proliferative cells of the basal layer renewing the epithelium, and terminally differentiated cells of the superficial layer sloughing off. In EoE, however, this continuum is skewed towards proliferative mechanisms, with an expansion of the basal layer observed (basal zone hyperplasia (BZH)), and a corresponding decrease in the amount of terminally differentiated, barrier forming cells. We thus sought to further understand the molecular mechanisms governing terminal esophageal epithelial differentiation in both homeostasis and disease. Prior research has shown the transcription factor Hypoxia-inducible Factor-1- alpha (HIF1α) to be decreased in EoE patients, with its genetic knock-down in an esophageal epithelial cell line (HIF1α-KD) leading to epithelial barrier dysfunction and differentiation deficits. The overall goal of this research was to thus further understand the underlying HIF1α-mediated mechanisms involved in the maintenance of the superficial epithelium of the EE that are dysregulated in EoE. We first sought to characterise markers of terminal esophageal epithelial differentiation, starting with involucrin (IVL), an established marker of differentiation within the skin. Immunofluorescent staining of IVL in human esophageal biopsies revealed IVL to be present in both suprabasal and superficial layers, whilst being absent from any basal cells. Using in vitro cultures, IVL was not found to be restrictive to late differentiating cells. We thus utilised a multi-factorial approach to identify other potential markers of terminal differentiation. Small proline rich protein 2A (SPRR2A) was found to be a high-fidelity marker of terminal differentiation both in vivo and in vitro. To further examine HIF1α-mediated terminal differentiation processes, fluorescent cell lines were generated whereby expression of a blue fluorescent protein (BFP) was under the control of either the IVL or SPRR2A promoter. These studies found IVL to be a suitable marker of HIF1α knock down (HIF1α-KD) differentiation defects, while SPRR2A was found to be unsuitable. To further understand how HIF1α-KD mediates decreased differentiation in EoE, we endeavoured to find downstream HIF1α targets important for the differentiation response. Dickkopf-1 (DKK-1) was found to be decreased in EoE and HIF1α-KD cells and localise to terminally differentiated superficial cells. Pharmacological inhibition of DKK-1 lead to decreased IVL expression. Chromatin immunoprecipitation (ChIP) and promoter analysis confirmed DKK-1 to be a novel HIF1α target gene, with recombinant DKK-1 treatment of three-dimensional (3D) HIF1α-KD cultures restoring faulty barrier and differentiation. As DKK-1 is an inhibitor of the pro-proliferative canonical Wingless-related integration site/Beta-Catenin (Wnt/β-Catenin) signalling pathway, we sought to examine a relationship between increased β-Catenin activity and differentiation defects. Treatment of cells with a β-Catenin agonist lead to decreased differentiation. Increased β- Catenin activation was observed in HIF1α-KD cells, a phenotype that was corrected with recombinant DKK-1 treatment. Furthermore, β-Catenin was found to be significantly decreased upon cellular differentiation. Combined, these findings show DKK-1 to be a novel HIF1α target gene, whose function in the superficial epithelium is to inhibit active β-Catenin signalling so as to allow terminal differentiation processes to occur. These studies indicate a novel signalling axis for therapeutic target in the treatment of EoE.