The One Health concept recognises that the health of humans is interconnected to the health of animals and the environment. It encourages multidisciplinary communication and collaboration with the aim of enhancing surveillance and research and developing integrative policy frameworks. Clostridium difficile (also known as Clostridioides difficile) infection (CDI) has long been viewed as a hospital-associated (HA) enteric disease mainly linked to the use of broad-spectrum antimicrobials that cause dysbiosis in the gut and loss of 'colonisation resistance'. However, since the early 2000s, the rate of communityassociated CDI (CA-CDI) has increased to ∼15% in Europe, ∼30% in Australia and ∼40% in the USA in populations often without obvious risk factors. Since the 1990s, it has become apparent that food animals are now a major reservoir and amplification host for C. difficile, including lineages of clinical importance. Cephalosporin antimicrobials, to which C. difficile is intrinsically resistant, were licensed for animal use in North America in 1990. By the second decade of the 21st century, there were reports of C. difficile contamination of food and the environment in general. Using whole-genome sequencing (WGS) and high-resolution typing, C. difficile isolates from humans, animals, food and the environment were proven to be genetically closely related and, in some cases, indistinguishable. This suggests possible zoonoses and/or anthroponoses, with contaminated food and the environment acting as the conduit for transmission between animals and humans. This paper summarises the key evidence that demonstrates the One Health importance of C. difficile.