Immune-mediated disorders such as allergy and autoimmunity are major public health problems. In the past 40 years the incidence of these diseases has risen dramatically in developed countries. Epidemiological studies have revealed a clear correlation between disease susceptibility and improvements in hygiene. For example, children with older siblings show a reduced prevalence of asthma, multiple sclerosis (MS), and Type 1 diabetes (T1D), and infants (<1year) that attend daycare centers show reduced incidence of atopic dermatitis and asthma. Whilst there is a clear genetic component to each of these diseases, development is a result of a complex interplay between genes, environment, and the immune system. Therefore, in genetically stable populations changes in the environment, which impact on immune development and regulation, must account for the observed increase in disease susceptibility. The “Hygiene Hypothesis” originally proposed that the increased incidence of allergic disease was due to decreased microbial exposure early in life, particularly during early childhood as the immune system develops. However, the immune mechanisms underlying the hygiene hypothesis remain elusive and our understanding of how hygiene, pathogen exposure, and environmental bacterial diversity might lower the susceptibility to allergy and autoimmunity is extremely limited. This research project will make use of state-of-the-art germ-free and gnotobiotic (controlled microbial status) animal models to elucidate the precise immunological mechanisms that are affected by decreased microbial exposure. Understanding the way in which environmental microbes influence immune development and regulation will lay the groundwork for treatment regimes aimed at reducing the rise in allergic and autoimmune diseases. More importantly, a greater understanding of how hygiene levels impact on disease development should lead to a greater ability to prevent, and not just treat, such diseases.