Abstract  In the rich, developed parts of the world there has been a steady and simultaneous increase in at least three groups of disease: (1) allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohns disease and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and multiple sclerosis). Because the medical world is so compartmentalised it was some time before the connection between these increases was noticed and understood. There is now evidence that the simultaneous increase in these diseases of immunodysregulation is at least partly attributable to malfunction of regulatory T cells (Treg). This paper provides an overview of relevant work in each of these fields of medicine (though with emphasis on the allergic disorders), and concludes that the increasing failure of Treg is a consequence of diminished exposure to certain micro-organisms that are old friends, because of their continuous presence throughout mammalian evolution. These organisms, which include saprophytic mycobacteria, helminths and lactobacilli, are recognised by the innate immune system as harmless, and as adjuvants for Treg induction. Polymorphisms of components of the innate immune system such as TLR2 and NOD2 appear to define subsets of the population that will develop immunoregulatory disorders when living in the modern environment. A further role of the old friends and of the Treg that they induce might be to maintain the levels of regulatory IL-10 secreting macrophages and antigen-presenting cells, which are depleted in asthma and Crohns disease. These concepts are leading to novel therapies based on harmless organisms or their components. Phase I/II clinical trials have yielded some statistically significant results, and phase II trials are in progress.