Progressive lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients. CF lung disease is characterised by endobronchial inflammation sustained by bacterial infections and an ongoing accumulation of airway neutrophils. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment. Among various proteases released by airway cells, elastase is considered to play the major role in CF lung disease. Based on this concept, several therapeutic approaches have been developed to inhibit free elastolytic activity, including small synthetic chemical compounds, semi-synthetic inhibitors and natural inhibitors of free elastase. The present review summarises and discusses the pathophysiological rationales, methodological requirements and clinical implications of inhibition of airway proteases in cystic fibrosis lung disease. Copyright©ERS Journals Ltd 2008.