The discovery of Mycoplasma genitalium in 1980–1981 eventually led to it becoming recognized as an important cause of non-gonococcal urethritis in men and also some genital tract diseases in women. Subsequent to the original isolation, further attempts failed over the next decade and reliable detection only became possible with the use of nucleic acid amplification techniques. Although tetracyclines, particularly doxycycline, were the first choice for treatment of non-gonococcal urethritis prior to the finding of M. genitalium, they were unsatisfactory for the treatment of M. genitalium-associated disease; the organisms were often not eliminated leading, for example, to chronic urethritis. However, the introduction of azithromycin, used as single-dose therapy for chlamydial infections, resulted in clearance of the mycoplasmal organisms from the genital tract and clinical recovery without the development of chronic disease. Nevertheless, such success was short-lived as M. genitalium, through mutation, began to develop resistance to azithromycin and M. genitalium mutants also began to circulate in some populations. In an attempt to counteract this, clinicians should give extended therapy, and in the future, microbiologists, using real-time PCRs, might be able to determine the existence of resistant strains in the local population and so advise on the most appropriate antibiotic. Other than azithromycin, there are a few options, moxifloxacin being one, although the recently reported resistance to this antibiotic is disturbing. In the short to medium term, combination therapy and/or the advent of a new antibiotic might abate the spread of resistance, but in the long term, there is potential for increasing prevalence of untreatable M. genitalium disease. In the future, attempts to develop a vaccine and, of equal importance, one to Chlamydia trachomatis, would not be out of place.