Background and AimsCommunity-acquired pneumonia (CAP) is a common infectious disease affecting children and adults of any age. Mycoplasma pneumoniae has emerged as leading causative agent of CAP in some region, and the abrupt increasing resistance to macrolide that widely used for management of M. pneumoniae has reached to the level that it often leads to treatment failures. ObjectiveWe aim to discuss the drivers for development of macrolide-resistant M. pneumoniae, antimicrobial stewardship and also the potential treatment options for patients infected with macrolide-resistant M. pneumonia. MethodsThe articles in English and Chinese published in Pubmed and in Asian medical journals were selected for the review. ResultsM. pneumoniae can develop macrolide resistance by point mutations in the 23S rRNA gene. Inappropriate and overuse of macrolides for respiratory tract infections may induce the resistance rapidly. A number of countries have introduced the stewardship program for restricting the use of macrolide. Tetracyclines and fluoroquinolones are highly effective for macrolide-resistant strains, which may be the substitute in the region of high prevalence of macrolide-resistant M. pneumoniae. ConclusionThe problem of macrolide resistant M. pneumonia is emerging. Antibiotic stewardship is needed to inhibit the inappropriate use of macrolide and new antibiotics with a more acceptable safety profile for all ages need to be explored.