In the next few years, it is likely that we shall have several new therapies for severe asthma. For the clinician to understand how to select the right therapy for the right patient, we shall need to better understand the phenotype-specific mechanistic role of different elements of the immune response and to have biomarkers of these mechanisms, as it is likely that some changes in airway inflammation and remodeling will contribute more to exacerbation risk, whereas others might be more related to symptoms or lung function. For example, in contrast to the success of anti-IL5R in phase III studies, the anti-IL-13 biologic lebrikizumab was only successful in achieving its primary outcome of reducing asthma exacerbations in one of two pivotal phase III studies. However, lebrikizumab has consistently improved lung function, perhaps in part due to its effects on airway smooth muscle rather than eosinophilic inflammation, and improvements were greatest in those patients with an activated IL-13 pathway, as evidenced by increased blood levels of periostin. The outcome of phase III studies of another anti-IL-13 therapy, tralokinumab, are awaited, but earlier studies again demonstrated a more consistent effect on lung function, with the greatest reductions in exacerbations observed in those with bronchodilator reversibility and elevated blood periostin or dipeptidyl-peptidase-4 levels. Dupilumab shows promise and targets both IL-4 and IL-13 signaling through anti-IL4Rα, which might have a more profound effect on airway inflammation. Importantly, it is unknown whether these approaches reduce eosinophilic airway inflammation. Fevipiprant, a small-molecule type 2 prostaglandin D2 receptor inhibitor, has demonstrated beneficial effects on lung function and eosinophilic inflammation in sputum and bronchial biopsy samples. Whether this translates into a benefit in exacerbation frequency is unknown, and findings from phase III studies are awaited.