In general, asthma runs a variable course. However, there are children with asthma who are at risk for progressive disease that can lead to failure to attain peak lung growth and eventually can result in clinical and functional impairment. We present a case of a 14-year-old girl who has demonstrated a deterioration in lung function at least in the past 6 years. This has been associated with increasing medication requirements, including chronic oral corticosteroid and a steroid-sparing medication, the presence of comorbidities, and the occurrence of frequent exacerbations. The patient has evidence of airway inflammation and remodeling based on biomarkers and biopsy findings. It remains a challenge to determine patients at risk for irreversible airflow obstruction, presumably a result of airway remodeling. Histopathologic studies from biopsy samples provide the best evidence for this. However, bronchoscopy and biopsy require technical expertise and cannot be routinely used. Clinically, once a patient increases medication requirements, this should serve as a marker of disease progression. Biomarkers of airway inflammation such as exhaled nitric oxide, exhaled breath condensates, and induced sputum analysis may have the potential to monitor disease progression. Additional efforts are necessary to understand the mechanisms involved in this phenomenon and to discover specific modalities of treatment to target the structural changes of airway remodeling.