The One Health concept is a worldwide strategy for interdisciplinary collaboration and communication in all aspects of healthcare for humans, animals and the environment. In recent years, 70% of emerging or re-emerging infections have been vector-borne or zoonoses - animal diseases transmissible to humans. Clostridium difficile infection (CDI) should always have been considered a zoonosis, either direct or indirect. It would appear that C. difficile colonises the gastrointestinal tracts of all animals during the neonatal period, multiplies and is excreted, but cannot/does not compete well when other bacterial species start to colonise. Adult humans treated with antibiotics fool C. difficile into thinking it is colonising a neonatal gut. In the 1980s and 90s, there was an expansion of CDI in hospitals that continues today driven by cephalopsorins. Since 1990 in North America, cephalosporins have been licensed for use in food animals. Thus there has been amplification of C. difficile in food animals, with subsequent contamination of meat, and vegetables grown in soil containing animal faeces. In some animals such as piglets, there is overt disease with significant impact on industry. Animal strains of C. difficile are now infecting humans. C. difficile RT 027 probably moved from animals to humans in North America in the early 1990s, initially causing infections in the community at a time when community-acquired (CA) CDI was thought rare. Mutation to FQ resistance at about this time and excessive use of FQs drove RT 027 spread in North America once it entered the hospital system. This is now occurring with RT 078, another animal strain. C. difficile continues to expand in food animal populations, driven by cephalosporin use, and animal strains of C. difficile are driving the world-wide epidemic of CA-CDI. It is essential that a One Health approach is used to solve this problem.