© 2006 by Nova Science Publishers, Inc. All rights reserved. Cystic fibrosis is a lung disease characterized by abnormal epithelial ion transport leading to a neutrophil-dominant inflammation. Neutrophils migrate into the airway lumen under the stimulation of immune factors secreted by airway epithelial and immune cells following bacterial infection. In CF, this neutrophil-dominant inflammation has been related to a variety of mechanisms, including the hypersecretion of IL-8 by airway epithelial cells. As a consequence of this neutrophil influx, neutrophil elastase is the predominant neutrophil-derived protease found in CF sputum and the determination of its concentration at the surface of the airway epithelium, in parallel with neutrophil counts, is used as a marker of inflammation severity. Due to its elevated concentration and its catalytic activity, neutrophil elastase has deleterious effect on CF lung function. This enzyme: 1) impairs mucociliary clearance by enhancing mucins synthesis and secretion and by affecting ciliary beating; 2) affects lung architecture by inducing goblet cell metaplasia, cell cycle arrest and increasing epithelial permeability; 3) promotes a sustained primary inflammatory response by increasing IL-8 production via the activation of toll-like receptors (TLR2 and TLR4) and the epithelial growth factor receptor, 4) activates metalloproteases responsible of matrix degradation and decreases the endogenous lung anti-protease activity; 5) decreases the efficiency of the innate immune response by degrading receptors involved in pathogen opsonization. Recently, neutrophil elastase has also been reported to modulate ion transport of airway epithelial cells by stimulating epithelial sodium reabsorption through epithelial sodium channels (ENaC). All these observations suggest that neutrophil elastase is a key mediator in the crosstalk between immune and epithelial cells occurring during inflammation. This chapter proposes to summarize neutrophil elastase actions at the surface of the respiratory epithelium to better understand how this enzyme contribute to CF etiology and to highlight potential therapeutic targets in the treatment of this chronic pulmonary disease.