Mycoplasma pneumoniae is an important pathogen of the upper and lower respiratory tracts of children and adults. Historically, it has been susceptible in vitro to macrolides, tetracyclines, and fluoroquinolones. Standardized methods for performance and interpretation of in vitro susceptibility tests have now been published for M. pneumoniae and mechanisms of acquired resistance to macrolides have been shown to be due to mutations in the 23S rRNA gene. Emergence and widespread dissemination of clinically significant high-level macrolide resistance in Asia and documentation of its occurrence to a lesser extent in several European countries and the United States during the past decade is worrisome since treatment options for children are limited. This article summarizes the current status of antimicrobial susceptibility testing, mechanisms of antimicrobial resistance, epidemiology of macrolide resistance and treatment alternatives for pediatric infections caused by M. pneumoniae. © 2013 Bentham Science Publishers.