The revolution in cystic fibrosis treatment is rooted in tremendous interdisciplinary research efforts, which led in recent years to significant progress in precision medicine. Since 2004, a key annual event for the CF research community is the ECFS Basic Science Conference (BSC), which is an ideal venue for deep discussions around topical subjects and fosters basic CF-related research in Europe and beyond. This special issue explores topics that were featured at the 16th ECFS BSC, held in Dubrovnik in March 2019 and provides an overview of recent progress in various fields for understanding disease mechanisms, developing relevant cell and animal models and designing breakthrough therapies. The special issue also identifies a number of the key issues and challenges in the future development of transformative therapies for all patients with CF.