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Highly effective modulator therapies (HEMT) improve the lives of many people with cystic fibrosis (PwCF) by correcting the structure and function of the defective CFTR channel at the molecular level. Despite these advancements, a subset of patients\u2014termed modulator-refractory CF\u2014continues to experience two or more pulmonary exacerbations per year requiring hospitalization or intravenous antibiotics, regardless of other modulator benefits. This underrecognized group represents an emerging challenge within the CF community. We discuss the benefits and limitations of current CFTR modulator therapies and the urgent need to investigate this emerging at-risk population. While HEMT improves lung function, decreases exacerbations, reduces the need for lung transplantation, and lowers mortality, increasing evidence shows that not all patients benefit equally. At the University of Virginia, nearly 6% of adults with CF exhibit the modulator-refractory phenotype. The driving factors of modulator-refractory CF are likely multifactorial, including genetic variations, variable immune responses, preexisting bronchiectasis, microbiological colonization, preexisting comorbid conditions, and environmental and socioeconomic factors. This perspective review recognizes and defines modulator-refractory CF as a distinct emerging clinical phenotype in the post-modulator era. Understanding this phenotype is crucial for reducing morbidity and mortality, and for improving the quality of life for PwCF. Raising awareness of modulator-refractory CF will help the community address this population and perform further research to identify causes. The emergence of modulator-refractory CF highlights a significant gap in our current treatment landscape and provides an opportunity to develop innovative therapeutic strategies that may benefit the entire CF community, ensuring that no person with CF is left behind.<\/jats:p>","DOI":"10.1177\/17534666241297877","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T02:03:34Z","timestamp":1731636214000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["Modulator-refractory cystic fibrosis: Defining the scope and challenges of an emerging at-risk population"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-0640","authenticated-orcid":false,"given":"Lindsay","family":"Somerville","sequence":"first","affiliation":[{"name":"University of Virginia, 1215 Lee Street, Charlottesville, VA 2908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Borish","sequence":"additional","affiliation":[{"name":"University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imre","family":"Noth","sequence":"additional","affiliation":[{"name":"University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9055-3247","authenticated-orcid":false,"given":"Dana","family":"Albon","sequence":"additional","affiliation":[{"name":"University of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"bibr1-17534666241297877","unstructured":"Cystic Fibrosis Foundation Patient Registry 2021 Annual Data Report. 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