BACKGROUND Despite the amount of new information, the most effective approach for the diagnosis and treatment of Mycoplasma pneumoniae infections is not established. In this narrative review the pharmacological options for macrolide-resistant (ML) M. pneumoniae infections in children are discussed. METHODS Despite significant improvement in the diagnosis and in the definition of diseases potentially associated with this pathogen, not all the problems related to M. pneumoniae infection are solved. True epidemiology of M. pneumoniae diseases and the real role of this pathogen in extra-respiratory manifestations is still unestablished. This reflects on therapy. It is not known whether antibiotics are really needed in all the cases, independently of severity and localization. The choice of antibiotic therapy is debated as it is not known whether ML resistance has clinical relevance. Moreover, not precisely defined is the clinical importance of corticosteroids for improvement of severe cases, including those associated with ML-resistant strains. CONCLUSIONS Improvement in M. pneumoniae identification is mandatory to reduce antibiotics overuse , especially in the presence of ML-resistant strains. Priority for future studies includes the evaluation of the true benefit of therapeutic approaches including corticosteroids in patients with severe CAP and in those with extra-respiratory M. pneumoniae diseases.