Cystic fibrosis (CF) is chronic lung disease characterized by an unrelenting neutrophil-predominant airway inflammatory response. This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis. While many components of the immune response in CF have been well-characterized, recent data suggests that small molecules may play an important and underappreciated role in this inflammation. This review will examine two novel molecules: proline-glycine-proline (PGP) and high mobility group box protein-1 (HMGB1), and their potential impact in CF lung disease. This review will provide a brief overview of CF lung disease and background on both HMGB1 and PGP. It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals. Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.