Cystatin SN, encoded by CST1, belongs to the type 2 (T2) cystatin protein superfamily. In the past decade, several publications have highlighted the association between cystatin SN and inflammatory airway diseases including chronic rhinosinusitis, rhinitis, asthma, chronic obstructive pulmonary disease, and chronic hypersensitivity pneumonitis. It is, therefore, crucial to understand the role of cystatin SN in the wider context of T2 inflammatory diseases. Here, we review the expression of cystatin SN in airway-related diseases with different endotypes. We also emphasize the physiological and pathological roles of cystatin SN. Physiologically, cystatin SN protects host tissues from destructive proteolysis by cysteine proteases present in the external environment or produced via internal dysregulated expression. Pathologically, the secretion of cystatin SN from airway epithelial cells initiates and amplifies T2 immunity and subsequently leads to disease. We further discuss the development of cystatin SN as a T2 immunity marker that can be monitored noninvasively and assist in airway disease management. The discovery, biology, and inhibition capability are also introduced to better understand the role of cystatin SN in airway diseases.Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.