Listeria monocytogenes is the etiologic agent of the life-threatening foodborne illness listeriosis and a model organism for the study of intracellular parasitism. Our recent studies on L. monocytogenes have revealed a novel invasion mechanism. In this mechanism, perforation of the host cell plasma membrane by the L. monocytogenes cholesterol-dependent cytolysin (CDC) listeriolysin O is sufficient to activate F-actin-dependent internalization of the bacterium. This invasion pathway is not uniquely activated by listeriolysin O since the heterologous CDC pneumolysin also induces the internalization of L. monocytogenes or 1 μm latex beads. The molecular machinery that underlines this novel invasion mechanism is still unsolved. It was proposed that in response to perforation by sublytic concentrations of pore-forming toxins, the plasma membrane is efficiently repaired through a multistep process leading to F-actin-independent endocytosis and that pathogens may hijack this endocytic pathway to gain entry into host cells. However, studying membrane repair, cytoskeletal remodeling, various signaling and endocytic molecules in cells exposed to pore-forming toxins revealed that such a model is insufficient to account for pathogen uptake. We found that L. monocytogenes endocytosis downstream from membrane perforation by listeriolysin O is either unrelated to the membrane repair process or that the current model for membrane repair is incomplete; and therefore we propose a new model. Importantly, this invasion mechanism is relevant to numerous pathogens because pore-forming proteins are present on viral particles or produced by numerous bacterial and eukaryotic intracellular pathogens.