Neutrophil (PMN) transmigration across mucosal epithelia is a hallmark of inflammatory conditions, such as ulcerative colitis and Crohn's disease. PMN accumulation within epithelial crypts and in the intestinal lumen directly correlates with clinical disease activity and epithelial injury. Currently, the mechanisms by which PMNs migrate across mucosal epithelia are incompletely understood and a better understanding of this process will likely provide new insights into novel treatment strategies for inflammatory bowel disease. In this article, we discuss current advances that define PMN transepithelial migration, specifically focusing on PMN–epithelial adhesive interactions and signaling events. We also describe how these interactions might be specifically targeted for the development of therapeutic strategies to manage mucosal inflammation.