The discovery that eosinophilia and steroid responsiveness are dominant signals in patients with asthma led to the conclusion that inflammation characterized by up-regulation of the type 2 cytokines that mediate eosinophilia (IL -4, -5, and -13) (type 2 inflammation) is central to asthma pathogenesis in all patients and resulted in a singular emphasis on animal models of type 2 inflammation to unravel disease mechanisms. This in turn led to great progress in identifying drug targets and in developing inhibitors of type 2 inflammation. Despite this significant and clinically important progress, there has been a growing body of evidence that airway type 2 inflammation is not a ubiquitous pathologic feature of asthma and a growing acceptance that the type 2-centric asthma paradigm has held back understanding of mechanisms of disease in patients who do not have type 2 inflammation (helper T-cell type 2 [Th2]-low asthma). This “tyranny of the dominant paradigm” effect means that asthma clinicians have no effective controller treatments to offer their many patients with Th2-low asthma. It also means that asthma researchers are struggling to understand the mechanisms of disease that operate in Th2-low asthma and how these mechanisms might be modeled in vitro and in vivo to identify novel drug targets and provide a broader range of asthma treatments.