Activated ILC2s accumulate in the lung in asthma and promote disease via 2 mechanisms: (a) direct activation by TSLP (thymic stromal lymphopoietin), IL-33, and IL-25 in response to allergens, viruses, and environmental stress and (b) IgE-dependent antigen responses, which induce mast cell secretion of lipid mediators, such as PGD₂ (prostaglandin D₂) and CysLTs (cysteinyl leukotrienes), to attract and activate ILC2s. ILC2s also promote type 2 responses in allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyposis (CRSwNP), where they accumulate in polyps. Seasonal increases in ILC2s in AR are suppressed by allergen immunotherapy. Montelukast (a CysLT₁ antagonist), approved for asthma and AR, inhibits ILC2 activation. β₂ Adrenergic receptor (β₂AR) agonists negatively regulate ILC2s in asthma by inhibiting their proliferation and effector function. In both asthma with or without AR and CRSwNP, systemic steroids decrease ILC2 cytokine production and promote ILC2 apoptosis. Dupilumab inhibits IL-4Rα, the shared receptor of IL-4 and IL-13, and is approved in asthma and CRSwNP. Anti–IL-5 mAbs (mepolizumab, benralizumab, reslizumab) are approved in asthma and are being tested in CRSwNP. CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists to block PGD₂-mediated ILC2 trafficking as well as antibodies against TSLP and IL-33 to inhibit ILC2 activation are in testing. Illustrated by Rachel Davidowitz.