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Many species of mycobacteria that normally live as environmental saprophytes, the environmental mycobacteria (EM), are opportunist causes of disease in humans and animals. Many, but not all, cases are associated with some form of immune deficiency. An increasing number of species and clinical presentations are being described, and advances are being made in the understanding of the underlying predisposing factors. In recent years, four aspects of EM disease have become particularly relevant to human health: (1) the high prevalence of EM disease in patients with AIDS; (2) the emergence of Buruli ulcer, an ulcerative skin disease caused by Mycobacterium ulcerans, as the third most prevalent mycobacterial disease; (3) the effect of infection by EM on the immune responses to BCG vaccination and on the course and outcome of tuberculosis and leprosy; (4) the controversy over the involvement of mycobacteria, notably M. avium subspecies paratuberculosis, in human inflammatory bowel disease. These aspects change the status of EM from mere curiosities to important direct, indirect, and putative causes of serious and increasingly common human disease.