Purpose of review Studies completed in the last decade provide new insights into the role of the epithelial glycocalyx in maintaining ocular surface barrier function. This review summarizes these findings, their relevance to allergic and infectious disease, and highlights the potential benefits of exploiting the modulation of barrier integrity for therapeutic gain. Recent findings The molecular components sealing the space between adjacent ocular surface epithelial cells, such as tight junctions, have been extensively characterized, and their contribution to the paracellular barrier established. A second layer of protection—the transcellular barrier—is provided by transmembrane mucins and their O-glycans on the glycocalyx. Cell surface glycans bind carbohydrate-binding proteins to promote formation of complexes that are no longer thought to be a static structure, but, instead, a dynamic system that responds to extrinsic signals and modulates pathogenic responses. While functioning as a protective mechanism to maintain homeostasis, the glycocalyx also restricts drug targeting of epithelial cells. Summary The traditional model of intercellular junctions protecting the ocular surface epithelia has recently been expanded to include an additional glycan shield that lines apical membranes on the ocular surface. A better understanding of this apical barrier may lead to better management of ocular surface disease.