Selected bacteria, viruses, parasites and nonliving, immunologically active microbial substances prevent autoimmune diabetes in animal models. Such agents might also have a protective effect in humans by providing immune stimuli critical during childhood development. The 'hygiene hypothesis' proposes that reduced exposure to environmental stimuli, including microbes, underlies the rising incidence of childhood autoimmune diseases, including type 1 diabetes mellitus (T1DM). This hypothesis is supported by data that highlight the importance of infant exposure to environmental microbes for appropriate development of the immune system, which might explain the observation that administration of microbes or their components inhibits autoimmune disease in animals. This finding raises the possibility of using live, nonpathogenic microbes (for example, probiotics) or microbial components to modulate or 're-educate' the immune system and thereby vaccinate against T1DM. Progress has been assisted by the identification of receptors and pathways through which gut microbes influence development of the immune system. Such mechanistic data have moved a field that was once regarded as being on the scientific fringe to the mainstream, and support increased funding to advance this promising area of research in the hope that it might deliver the long awaited answer of how to safely prevent T1DM.