Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They represent a potential therapeutic option for asthma, a chronic inflammatory disorder characterised by airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Results from clinical trials, however, have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration, dose, and differing outcome measures. Recent evidence suggests improved effectiveness of macrolides in patients with sub-optimally controlled severe neutrophilic asthma and in asthma exacerbations. We examine the evidence from clinical trials and discuss macrolide properties and their relevance to the pathophysiology of asthma. At present, the use of macrolides in chronic asthma or acute exacerbations is not justified. Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide-responsive subgroup. Future clinical trials should target this subgroup and place emphasis on clinically relevant outcomes such as asthma exacerbations.