Neutrophil (also known as polymorphonuclear leukocyte, or PMN) transepithelial migration and accumulation at mucosal surfaces is a hallmark of many inflammatory conditions. This process correlates directly with clinical disease activity and epithelial injury. Currently, the mechanisms that define PMN epithelial interactions during an inflammatory response are not completely understood. This review provides an overview of the consequences of PMN infiltration into epithelial tissues and highlights molecular details of PMN epithelial interactions during transmigration. A better understanding of this process will likely provide new insights into developing organ-specific treatment strategies to reduce the deleterious consequences of epithelial inflammation.