Severe asthma is a heterogeneous disease with substantial unmet clinical need. Airway damage and remodelling is a consequence of complex host–environment interactions and is considered to be the cardinal feature leading onto the development and persistence of airflow obstruction. In this review, we shall bring together recent insights into the causes of airway damage and remodelling that propose key roles for pathogens and mechanical damage in addition to allergens, underlying genetic susceptibility, inflammatory and structural cell interactions, and impaired resolution of damage. We shall consider the consequences of airway remodelling in terms of airway geometry, mechanics and clinical expression of disease. Understanding the causes and consequences of airway damage and remodelling will shed light upon the structure–function relationships required to begin to unravel the complexity of severe asthma and will enable us to target current and novel therapies as we begin to move towards realizing personalized medicine.