Mycoplasma genitalium is an etiological agent of sexually transmitted infections, but due to its fastidious growth requirements, only a few M. genitalium strains are available for determination of the activity of currently used and new antimicrobial agents.Recent clinical trials have demonstrated that treatment with azithromycin has decreasing efficacy due to an increasing prevalence of macrolide resistance, which is likely to be attributed to the widespread use of 1 g single dose azithromycin. Second line treatment with moxifloxacin is similarly under pressure from emerging resistance. The era of single dose monotherapy for uncomplicated STIs such as M. genitalium and N. gonorrhoeae, while convenient for patients and physicians, has been associated with escalating resistance and treatment failure and is now drawing to a close. There is a critical need for trials of combinations of existing registered drugs and new antimicrobial compounds, implementation of diagnostic testing combined with molecular detection of resistance, and antimicrobial surveillance.