The pathogenesis of bacillary dysentery can be studied at different levels of integration of the cellular components that constitute the colonic mucosal barrier. We considered the interaction of Shigella flexneri in three experimental systems that provide complementary information and a scheme of events occurring in human colorectal mucosa as Shigella invasion proceeds. Interaction of S. flexneri with individual epithelial cells shows a series of events in which the bacterium, upon contact with the cell surface, releases a set of Ipa proteins (i.e. invasins) through a specialized, activable, type-III secretory apparatus (i.e. Mxi/Spa). Via a complex signaling process, these invasins cause major rearrangements of the subcortical cytoskeletal network which allow bacterial entry by a macropinocytotic event. Then the bacterium lyses its phagocytotic vacuole and initiates intracytoplasmic movement, due to polar assembly of actin filaments caused by a bacterial surface protein, IcsA. This allows very efficient colonization of the host cell cytoplasm and passage to adjacent cells via protrusions which are engulfed by a cadherin-dependent process. However, when invasive Shigella are deposited on the apical side of polarized monolayers of human colonic cells, they appear unable to invade, indicating that bacteria need to reach the subepithelial area to invade the epithelium. In this system, it has been shown that transepithelial signaling caused by apical bacteria induces adherence and transmigration of basal polymorphonuclears (PMN), thus disrupting the monolayer permeability and facilitating bacterial invasion. LPS accounts for a large part of this transepithelial signalization to PMN. Such a process could account for invasion in intestinal crypts. Finally, models of infection, such as the rabbit ligated intestinal loop show that initial bacterial entry occurs essentially via M cells of the follicular associated epithelium. It then causes apoptosis of macrophages located in the follicular dome, inducing release of IL-1 beta which, in turn, initiates inflammation, leading to destabilization of the epithelial structures as modeled above. These data can now be used to understand the mechanisms of mucosal protection against bacillary dysentery.