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The aerobic actinomycetes are soil-inhabiting microorganisms that occur worldwide. In 1888, Nocard first recognized the pathogenic potential of this group of microorganisms. Since then, several aerobic actinomycetes have been a major source of interest for the commercial drug industry and have proved to be extremely useful microorganisms for producing novel antimicrobial agents. They have also been well known as potential veterinary pathogens affecting many different animal species. The medically important aerobic actinomycetes may cause significant morbidity and mortality, in particular in highly susceptible severely immunocompromised patients, including transplant recipients and patients infected with human immunodeficiency virus. However, the diagnosis of these infections may be difficult, and effective antimicrobial therapy may be complicated by antimicrobial resistance. The taxonomy of these microorganisms has been problematic. In recent revisions of their classification, new pathogenic species have been recognized. The development of additional and more reliable diagnostic tests and of a standardized method for antimicrobial susceptibility testing and the application of molecular techniques for the diagnosis and subtyping of these microorganisms are needed to better diagnose and treat infected patients and to identify effective control measures for these unusual pathogens. We review the epidemiology and microbiology of the major medically important aerobic actinomycetes.