Objective: To review the literature concerning the use of hypertonic saline (HS) in patients with cystic fibrosis and explain the rationale for its use. Data Sources: A MEDLINE search was conducted through February 2007. Search terms included hypertonic saline, mucociliary clearance, cystic fibrosis, and human DNASE 1 protein. Additional data were identified through subsequent bibliographic reviews. Study Selection And Data Extraction: All articles in English identified from the data sources were evaluated. Pertinent studies using HS in patients with cystic fibrosis were included in the analysis. Data Synthesis: Cystic fibrosis is caused by a deficiency in the cystic fibrosis transmembrane regulator gene, resulting in reduced chloride secretion and excessive sodium absorption. The most significant changes are seen in the airway lumen of the lungs. HS has been shown to improve mucociliary clearance versus placebo. A short-term efficacy trial showed a modest and variable increase in forced expiratory volume in 1 second (FEV 1 ) over a 2 week period (15.0 ± 16.0% from baseline vs 2.8 ± 13.1% with HS 6% and NaCI 0.9%, respectively; p = 0.004). A long-term efficacy trial of either HS 7% or NaCI 0.9% twice daily for 48 weeks has shown a modest sustained improvement in FEV 1 and a significantly increased exacerbation-free survival rato (76% vs 62% for HS 7% and NaCI 0.9%, respectively; p = 0.03). Conclusions: HS preceded by a bronchodilator is an inexpensive, safe, effective additional therapy in cystic fibrosis patients with stable lung function. Its use has been associated with a modest improvement in lung function and reduced frequency of pulmonary exacerbations.