Man has moved rapidly from the hunter-gatherer environment to the living conditions of the rich industrialised countries. The hygiene hypothesis suggests that the resulting changed and reduced pattern of exposure to certain critical micro-organisms, mostly derived from mud, animals and faeces, has led to disordered regulation of the immune system and, hence, to increases in chronic inflammatory disorders such as allergies, inflammatory bowel diseases and autoimmunity. Epidemiology, backed up by laboratory models, indicates that the relevant organisms are those that have very long associations with the mammalian immune system, traceable back to the Palaeolithic or earlier. Often, these organisms have been present as commensals (notably in the intestinal microbiota), environmental ‘pseudocommensals’, sub-clinical infections or asymptomatic carrier states, and the mammalian immune system is in a state of ‘evolved dependence’ on their continued presence. Several of these ‘Old Friends’, often operating primarily in the gut, act as modulators of dendritic cells and T cells, leading to the establishment of immunoregulatory circuits. Clinical trials are in progress to test living helminths (Trichuris suis and Necator americanus) in allergies, inflammatory bowel disease and multiple sclerosis. We can anticipate rapid increases in the use of these and other organisms or their components in novel types of therapy with applications in several branches of medicine. Probiotics tested in clinical trials targeting chronic inflammatory disorders have so far given unconvincing results, but if strains for these indications are selected on the basis of their ability to induce immunoregulation, and not merely imposed by companies that have intellectual property rights, we can anticipate rapid progress.