C. difficileis the primary cause for nosocomial infective diarrhoea. For a successful infection,C. difficilemust navigate between resident gut bacteria and the harsh host environment. The perturbation of the intestinal microbiota by broad-spectrum antibiotics alters the composition and the geography of the gut microbiota, deterring colonization resistance, and enablingC. difficileto colonize. This review will discuss howC. difficileinteracts with and exploits the microbiota and the host epithelium to infect and persist. We provide an overview ofC. difficilevirulence factors and their interactions with the gut to aid adhesion, cause epithelial damage and mediate persistence. Finally, we document the host responses toC. difficile, describing the immune cells and host pathways that are associated and triggered duringC. difficileinfection.