Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia. In the past, M. pneumoniae was sensitive to macrolide antibiotics, and M. pneumoniae pneumonia (MPP) was usually a benign and self-limiting disease. However, despite use of the appropriate antibiotics, persistent fever and clinical deterioration may occur, leading to severe disease. Two major complicated conditions that may be clinically encountered are macrolide-resistant MPP and refractory MPP. Regarding the epidemics in Taiwan, before 2017, the mean rate of macrolide resistance was below 30%. Notably, since 2018, the prevalence of macrolide-resistant MPP in Taiwan has increased rapidly. Macrolide-resistant MPP shows persistent fever and/or no radiological regression to macrolide antibiotics and may even progress to severe and complicated pneumonia. Tetracyclines (doxycycline or minocycline) or fluoroquinolones are alternative treatments for macrolide-resistant MPP. Refractory MPP is characterized by an excessive immune response against the pathogen. In this context, corticosteroids have been suggested as an immunomodulator for downregulating the overactive host immune reaction. Overuse of macrolides may contribute to macrolide resistance, and thereafter, an increase in macrolide-resistant MPP. Delayed effective antimicrobial treatment is associated with prolonged and/or more severe disease. Thus, the appropriate prescription of antibiotics, as well as the rapid and accurate diagnosis of MPP, is important. The exact starting point, dose, and duration of the immunomodulator are yet to be established. We discuss these important issues in this review.