Intercellular cell adhesion molecule-1 (ICAM-1) is an important member of the immunoglobulin superfamily (IgSF) of proteins that is centrally involved in trafficking of leukocytes to endothelial and epithelial barriers. This review will first outline the traditional role of ICAM-1 in regulating leukocyte trafficking across the endothelium. It will then deal with more novel aspects of epithelial ICAM-1 expression, particularly its induction upon apical epithelial surfaces and the potential functional consequences for both pathogen invasion and host defence. Signaling mechanisms related to structural rearrangements of the F-actin cytoskeleton which may facilitate pathogen adherence or invasion will also be briefly discussed in the context of antigen sampling through intestinal Peyer's patches. Finally, precedence for pathogen targeting of other IgSF members will be addressed, with emphasis on key cell-cell adhesion proteins as potential pathogen docking structures.