Mycoplasma genitalium has been causally linked with nongonococcal urethritis in men and cervicitis, pelvic inflammatory disease, preterm birth, spontaneous abortion, and infertility in women, yet treatment has proven challenging. To inform treatment recommendations, we reviewed English-language studies describing antimicrobial susceptibility, resistance-associated mutations, and clinical efficacy of antibiotic therapy, identified via a systematic search of PubMed supplemented by expert referral. Minimum inhibitory concentrations (MICs) from some contemporary isolates exhibited high-level susceptibility to most macrolides and quinolones, and moderate susceptibility to most tetracyclines, whereas other contemporary isolates had high MICs to the same antibiotics. Randomized trials demonstrated poor efficacy of doxycycline and better, but declining, efficacy of single-dose azithromycin therapy. Treatment failures after extended doses of azithromycin similarly increased, and circulating macrolide resistance was present in high levels in several areas. Moxifloxacin remains the most effective therapy, but treatment failures and quinolone resistance are emerging. Surveillance of M. genitalium prevalence and antimicrobial resistance patterns is urgently needed.