Since the drugs are in clinical use, therapeutic approaches to address F508del-CFTR defects by PDE5 inhibitors can be considered as a “low-hanging fruit” strategy in the drug discovery tree which could speed up their development as CF therapeutics, as compared to other agents that are under investigation only for CF therapy and for which further exploratory studies are needed before being streamed toward clinical testing. This evidence concerns the gene PDE5A and cystic fibrosis.