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Cystic fibrosis (CF) causes life-shortening respiratory and systemic disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. 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—termed modulator-refractory CF—continues 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. Plain language summary: Modulator-refractory cystic fibrosis: defining and understanding an emerging at-risk population Background: Cystic fibrosis (CF) is a genetic disease that primarily affects the lungs and other organs, significantly shortening life expectancy. Recent advances have led to the development of CFTR modulators, which correct the defective protein responsible for CF, resulting in improved lung health, reduced need for lung transplant, and longer life expectancy for many with CF.The Problem: Despite the success of modulators, about 6% of adults with CF do not respond well to these treatments. These individuals continue to experience severe lung problems, frequent hospitalizations, and a need for antibiotics. This group is identified as having modulator-refractory CF, meaning that their disease does not adequately respond to current modulator therapies.Possible Reasons for Modulator-Refractory Response: Several factors may contribute to modulator-refractory exacerbations, including: Medication utilization Genetic variations that may influence drug efficacy Variations in immune response Existing lung damage that has already occurred Persistent bacterial infections Co-existing health conditions that may interfere with modulators Living conditions and lifestyle choices Importance of Research: Understanding why some people with CF do not respond to modulator therapies is crucial for developing new strategies to help this at-risk population. By studying modulator-refractory CF, researchers hope to discover new treatments that can improve the lives of all people with CF, ensuring that no one is left behind as new therapies are developed.Conclusion: This article emphasizes the importance of focusing research and clinical efforts on understanding and addressing modulator-refractory CF. Increased awareness and targeted research are needed to find better treatments and support for this emerging population within the CF community. [ABSTRACT FROM AUTHOR]