Leukocyte migration occurs as a response to inflammatory signals and is an efficient host defense mechanism against invading pathogens. This innate defense response includes transendothelial and transepithelial migration of leukocytes to facilitate clearance of inflammatory stimuli. The endothelium lines the vascular system and forms the first barrier for leukocytes as they migrate out of the bloodstream. The epithelium largely separates organs from the external environment and forms a second barrier for leukocytes. These cellular barriers are comprised of complex intercellular junctions of different molecular composition. However, for barrier function to be maintained, these specialized intercellular junctions must not be destroyed during transmigration. Innate immune cells including monocytes, neutrophils and dendritic cells are all capable of a highly regulated transmigration response in order to accomplish their different functions. These cells exploit many common adhesive and signaling cascades to traverse cellular junctions. However, there are unique features of each type of leukocyte and barrier that determine specificity of the response. This review will focus on highlighting the mechanisms that leukocytes exploit to open these junctions.