Most cases of cystic fibrosis are caused by mutations that interfere with the biosynthetic folding of thecystic fibrosis transmembrane conductance regulator (CFTR), leading to the rapid degradation of CFTR molecules that have not matured beyond the endoplasmic reticulum (ER). The mechanism by which integral membrane proteins including CFTR are recognized and targeted for ER degradation and the proteolytic machinery involved in this process are not well understood. We show here that the degradation of both wild-type and mutant CFTR is inhibited by two potent proteasome inhibitors that induce the accumulation of polyubiquitinated forms of immature CFTR. CFTR degradation was also inhibited by coexpression of a dominant negative ubiquitin mutant and in cells bearing a temperature-sensitive mutation in the ubiquitin-activating enzyme, confirming that ubiquitination is required for rapid CFTR degradation.