Mycoplasma pneumoniae is one of the main pathogens causing community-acquired respiratory tract infections in children and adults. Macrolide (ML) antibiotics are recognized generally as first-choice agents for M. pneumoniae infections, and these antibiotics were thought to have excellent effectiveness against M. pneumoniae for many years. In 2000, however, M. pneumoniae showing resistance to macrolides was isolated from clinical samples obtained from Japanese pediatric patients with community-acquired pneumonia (CAP). Since then, prevalence of ML-resistant M. pneumoniae isolates in pediatric patients has increased rapidly. In 2007, ML-resistant M. pneumoniae isolates were obtained from Japanese adults with CAP; numbers of such isolates also have gradually increased in Japan. Recently, similar antimicrobial resistance in M. pneumoniae has begun to emerge worldwide. In this review, we focus on changes of ML-resistant M. pneumoniae from year to year and consider resistance mechanisms as well as clinical features of patients with resistant M. pneumoniae infection.