This study investigated the efficacy of in utero combination modulator therapy for cystic fibrosis (CF) using a ferret model with the F508del mutation, the most common mutation in the CF transmembrane conductance regulator (CFTR) gene. Researchers found that the F508del mutation in ferret CFTR led to severe folding and trafficking defects, partially restored by CFTR modulators. In utero treatment with ivacaftor/lumacaftor prevented meconium ileus at birth and sustained postnatal treatment improved survival and partially protected against pancreatic insufficiency in CF offspring. Withdrawal of treatment reestablished pancreatic and lung diseases. These findings suggest that in utero intervention with CFTR modulators may benefit individuals with F508del CF, highlighting the potential of this approach for clinical translation.