The autosomal recessive disease cystic fibrosis (CF) is caused by mutations in the gene coding for the CF transmembrane conductance regulator (CFTR) protein, a cAMP-activated chloride channel expressed at the apical membrane of epithelial cells. Although about 1000 different mutations have been identified, most CF patients carry the F508del mutation in at least one CFTR allele. F508del-CFTR is synthesized but is substantially retained as a core-glycosylated intermediate in the endoplasmic reticulum (ER), probably because of misfolding. The mutant protein is recognized by molecular chaperones involved in cellular quality control and rapidly targeted for proteasomal degradation. Although maturation of wild-type CFTR (wt-CFTR) is also inefficient at varying levels, depending on the cell type, there is increasing evidence that the two proteins acquire at least partially distinct conformations. However, the structural cues responsible for the conformational differences and the cellular mechanisms determining the endpoint for each conformer remain largely unclear. Some knowledge is emerging on CFTR membrane folding and on the role of this process of molecular chaperones, such as Hsp70/Hdj-1 and calnexin. The key players in the final decision on whether the protein will enter the secretory pathway or be degraded, however, remain unidentified. Here we discuss existing data on the interaction of molecular chaperones and CFTR, as well as their putative role on the degradation and processing of this polytopic membrane protein.