In recent years, it has become clear that innate immune cells termed neutrophils act as double-edged swords by playing essential roles in clearing infection but also causing tissue damage, yet being critical for wound healing. Neutrophil recruitment to sites of injured tissue or infection has been well studied, and many of the molecular events that regulate passage of leukocytes out of the microcirculation are now understood. However, after exiting the circulation, the molecular details that regulate neutrophil passage to end targets, such mucosal surfaces, are just beginning to be appreciated. Given that migration of neutrophils across mucosal epithelia is associated with disease symptoms and disruption of critical barrier function in disorders such as inflammatory bowel disease, there has been long-standing interest in understanding the molecular basis and functional consequences of neutrophil-epithelial interactions. It is a great honor that my work was recognized by the Rous-Whipple Award this past year, giving me the opportunity to summarize what we have learned during the past few decades about leukocyte interactions with epithelial cells.