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The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. This study found that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. These glucocorticoid-regulated genes were associated with multiple biological functions, including the immune response. To understand the direct role of GR signaling in the cornea, mice with conditional knockout of GRs in the corneal epithelium were generated. Mice lacking corneal GRs exhibited microphthalmia, loss of pupils, a deformed and opaque lens, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye., Competing Interests: Disclosure Statement None declared., (Published by Elsevier Inc.)