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As we characterize the clinical benefits of highly effective modulator therapy (HEMT) in the cystic fibrosis (CF) population, our paradigm for treating and monitoring disease continues to evolve. More sensitive approaches are necessary to detect early disease and clinical progression. This article reviews evolving strategies to assess disease control and progression in the HEMT era. This article also explores developments in pulmonary function monitoring, advanced respiratory imaging, tools for the collection of patient-reported outcomes, and their applicat