A growing body of basic and clinical science implicates the atypical bacterial pathogens Mycoplasma pneumoniae and Chlamydophila (formerly Chlamydia) pneumoniae as potentially important factors in asthma, although their exact contribution to asthma development and/or persistence remains to be determined. Evidence from human studies links both M pneumoniae and C pneumoniae to new-onset wheezing, exacerbations of prevalent asthma, and long-term decrements in lung function, suggesting that these organisms can play an important role in the natural history of asthma. Furthermore, animal models of acute and chronic infection with these organisms indicate that they have the ability to modulate allergic sensitization and pulmonary physiologic and immune response to allergen challenge. These findings raise the possibility that, in at least some individuals with asthma, antibiotic therapy might have a role in long-term treatment. While antibiotics do not currently have a defined role in the treatment of stable patients with chronic asthma, there is emerging evidence that asthma symptoms and biomarkers of airway inflammation can improve when patients who have atypical bacterial infection as a cofactor in their asthma are treated with macrolide antibiotics. Ongoing research into the importance of atypical pathogens in asthma will further elucidate whether these infections are important in disease development or whether their prevalence is increased in asthmatic subjects due to chronic airway inflammation or other, yet unidentified, predisposing factors. Current studies will further define the role of macrolide antibiotics in the treatment of stable patients with asthma, ultimately determining whether these therapeutic agents have a place in asthma management.