Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have changed the clinical landscape of cystic fibrosis (CF) by improving clinically significant outcome measures and quality of life of people with CF (pwCF). There are now long-term data showing improved 5-year survival with the use of ivacaftor, and the field continues to evolve at a rapid pace with the continued development of highly effective CFTR modulators. While the randomized controlled trials of CFTR modulators excluded patients with severe lung disease (forced expiratory volume in 1 second <40% predicted), observational data based on case reports and registry data show similar benefits in those with advanced lung disease. This has altered clinical practice particularly as it pertains to the role of lung transplantation in CF. This article describes the impact of highly effective modulator therapy (HEMT) on the natural history of CF and the influence on the timing of referral and consideration of listing for lung transplantation. CF clinicians play a pivotal role to ensure that the impetus of the CF foundation consensus guidelines to facilitate timely referral for lung transplantation is not lost among the excitement of anticipated sustained benefit from HEMT. While the widespread availability of elexacaftor/tezacaftor/ivacaftor over the past 2 years has been associated with a sharp drop in the number of people referred for consideration for lung transplantation and the number of people wait-listed for lung transplantation, it is difficult to accurately determine the true impact due to the confounding effect of the coronavirus disease 2019 pandemic. It is expected that lung transplantation will remain an important treatment for a smaller number of pwCF. Lung transplantation offers survival benefits in CF, and there remains an imperative to ensure timely consideration of lung transplantation in patients with advanced disease to further reduce the number of pwCF dying without consideration of lung transplant.