Cystic fibrosis (CF) is a chronic and debilitating genetic disease that occurs in over 70,000 people worldwide. Advances in treatment have led to significant improvements in longevity since the disorder was first described over half a century ago, and standardized care at CF care centers is central to these achievements. Traditional therapies for CF have focused on disease symptoms, including pancreatic enzyme replacement, mucus clearance from the lungs, treatment of lung infections, use of antiinflammatory agents and management of acute processes that periodically occur on a background of chronic therapies. Based on our understanding of early steps in the cascade leading to clinical CF, new therapeutic strategies are entering clinical trials that target upstream processes. These new therapies have the potential to dramatically change the face of CF, moving care from a symptom-based approach to a preventive, presymptomatic paradigm. This review will summarize recent progress in studies of airways hydrators and cystic fibrosis transmembrane conductance regulator (CFTR) modulators, focusing on medium and later phase clinical trials that target primary events in CF pathogenesis. Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.