Most cases of cystic fibrosis are caused by a deletion of phenylalanine 508 in the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR), which results in defects that can be partly rescued by low temperature or histone deacetylase (HDAC) inhibition. Pankow et al. used co-purifying protein identification technology (CoPIT) to analyse the interactomes of wild-type CFTR (WT CFTR) and ΔF508 CFTR, and identified a greater number of proteins as interacting with ΔF508 CFTR than with WT CFTR. Analysis of interactome dynamics following temperature shift or inhibition of HDACs revealed that functional rescue is associated with extensive remodelling of the ΔF508 CFTR-specific interactome. The authors identified key interactors that are lost during rescue or are crucial for CFTR biogenesis, providing valuable insight into the molecular mechanisms that underlie cystic fibrosis.