Background: The hygiene hypothesis refers to where modern living conditions are responsible for the increasing incidences of immune-related diseases including the development of inflammatory bowel diseases (IBD). Improved hygiene may result in decreased enteric microbiota diversity and dysbiosis, which may be responsible for the development of IBD. Key Messages: The rising incidence of IBD is well documented in developing regions of the world, in accordance with the hygiene hypothesis. What is unknown, however, is whether the hygiene hypothesis is applicable all over the world. Hygiene cannot be easily measured and proxy markers need to be used. These include regional data such as a country's gross domestic product or an individual's affluence or exposure to infection risk factors. A comparative case-control study of Caucasian Australian IBD subjects versus migrants from the Middle East to Australia identified that environmental risk factors are different in the 2 populations. Among Australian Caucasians, hygiene-related environmental risk factors are no longer relevant in the development of IBD. Given the country's high affluence, there has been high hygienic standard for several generations. However, migrants from less affluent countries exposed to hygiene-related environmental factors are at increased risks of developing IBD, especially in the second generation migrants born in the affluent country. Divergent risk factors include the use of antibiotics in childhood increasing the risk of IBD in developed societies but being a risk factor for developing IBD in migrants. In India, risk factors associated with infections were found to be positively associated with the development of ulcerative colitis, rather than protective. Conclusions: The hygiene hypothesis is not applicable to all populations worldwide, being most relevant in societies undergoing increasing affluence or following migration from less to more affluent countries. This review examines data from around the world that link the hygiene hypothesis with the development of IBD and in particular the divergent results arising from data from affluent countries versus less-affluent countries.