<p>Pneumonia, most often caused by a respiratory virus, is common in childhood. Mycoplasma pneumoniae also is detected frequently, particularly in older children in the era of pneumococcal conjugate vaccination. Despite recommendations for β-lactam antibiotics, macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are prescribed frequently to children with acute lower respiratory infection. However, the significance of detecting "atypical" pathogens, including M pneumoniae, in children remains contentious. Considering the potential for antibacterial and anti-inflammatory activities of macrolides, our understanding of the role of these drugs in acute and chronic infections and in inflammatory conditions is changing. Some observational data have revealed improved outcomes in adults and children with pneumonia who are prescribed macrolides, although its widespread use has led to increases in macrolide resistance in Streptococcus pneumoniae and M pneumoniae. Clinical trials to define the role of macrolides in pediatric acute respiratory infection must be prioritized.</p>