Cystic fibrosis (CF) infants are born with normal airway anatomy, and dilatation of mucus glands in smaller airways has been described as the earliest histological changes in the lung of patients. This and other evidence has led to the concept that the small airways may be the region demonstrating initial pathology. Studies clarifying this have been challenged by the lack of a clear definition of what constitutes “small airways" and the difficulties to find accurate measures to quantify and track abnormalities in this region of the lung. Dynamic lung function test are not ideally suited to capture small airway abnormalities as the overall surface area of the small airways is about 40 times greater than that of central airways. Measures that are linked to airway size therefore often fail to capture abnormalities in a disease such as cystic fibrosis that is unevenly distributed throughout the lung. This review summarizes our current understanding of the role of small airways in disease development in cystic fibrosis patients and describes the spectrum of diagnostic tools available to diagnose and follow small airway disease and highlight the opportunities as well as challenges of targeting small airways via aerosol therapy in CF patients.