Asthma is a lung disorder triggered by various airborne factors in susceptible individuals. Although generally controlled, asthma can be severe and difficult to treat. Presently, increasing numbers of pharmaceuticals capable of blocking or mimicking specific endogenous molecules are undergoing clinical trials in asthmatic individuals whose symptoms are poorly controlled despite adherence to guideline therapies. Unfortunately, only a few, meticulously selected patients have been found to minimally benefit. These findings not only confirm that the molecular pathogenesis of severe asthma is variable between patients but also suggest that each molecular defect is likely to contribute little on its own in each patient. We opine that therapies targeting a specific molecular defect are predestined to yield marginal effects in the treatment of severe asthma.