The endoplasmic reticulum (ER) is responsible for folding, modification and delivery of secretory proteins to their site of action (Glick, 2002; Haigh and Johnson, 2002). It contains a highly active protein quality control system (QC) which scans the folding process of secretory proteins and retains those species which are unable to fold (Elgaard and Helenius, 2003). They are eliminated by a process called ER associated degradation (ERAD) via the ubiquitin proteasome system (Kostova and Wolf, 2003). Malfunction of these processes is the cause of many diseases (Kostova and Wolf, 2002; Rutishauser and Spiess, 2002). One of the most common hereditary diseases amongst the white population which is directly linked to QC and ERAD is cystic fibrosis (Kerem et al., 1989; Riordan et al., 1989). Here a mutated ABC transporter and chloride channel of the apical membrane, the cystic fibrosis transmembrane conductance regulator (CFTR) is recognized by the QC as being malfolded and degraded via the ubiquitin-proteasome system. The most frequent mutation of CFTR which causes this effect is the deletion of a phenylalanine at position 508 in the first nucleotide binding domain (?F508). Interestingly even wild-type CFTR is very unstable and shows a degradation rate of about 70% (Jensen et al., 1995; Ward and Kopito, 1994). It is important to note that ?F508 CFTR can still function as a chloride channel (Dalemans et al., 1991) but due to QC and ERAD it fails to be transported to the apical plasma membrane. This could be overcome by lower temperature (Denning et al., 1992), high glycerol (Sato et al., 1996) or 4-phenylbutyrate (Rubenstein and Zeitlin, 2000). As none of these treatments is of therapeutic value other means have to be found to promote transport of mature ?F508 CFTR to the plasma membrane. Elucidation of the components of QC and ERAD which are responsible for the elimination of ?F508 CFTR is an important step in this direction. They may become targets for specific therapeutic manipulations to lead mutated but active CFTR to the cell surface. Previous studies have shown that the lectin calnexin interacts with CFTR in the ER lumen (Pind et al., 1994). Furthermore the bidirectional Sec61 translocon of the ER membrane was suggested to contribute to QC and ERAD (Bebök et al., 1998) as well as the cytosolic chaperones Hsp70/Hsc70, Hsp90 and the co-chaperone CHIP (Yang et al., 1993; Meacham et al.,1999; Loo et al., 1998; Meacham et al., 2001). Cellular QC and ERAD are highly conserved mechanisms from yeast to man (Ellgaard and Helenius, 2003; Kostova and Wolf, 2002, 2003). The ready availability of yeast mutants defective in QC and ERAD makes this organism a preferred model for investigation of these processes. Indeed the expression of CFTR in Saccharomyces cerevisiae has proven that the yeast components of QC and ERAD recognize this protein and degrade it via the proteasome in a ubiquitin dependent manner (Kiser et al., 2001; Zhang et al., 2001). These studies have uncovered the yeast ubiquitin conjugating enzymes Ubc6p and Ubc7p as well as the cytosolic Hsp70 as necessary components for the degradation of CFTR. Influence of the ubiquitin protein ligase Der3p/Hrd1p in CFTR degradation is somewhat controversial (Kiser et al., 2001; Zhang et al., 2001). Recently the mammalian counterparts of yeast Ubc6p, Ubc7p and Der3p/Hrd1p have been identified (Lenk et al., 2002; Fang et al., 2001; Tiwari and Weissman, 2001). Thus Saccharomyces cerevisiae proves to be an excellent model organism to further investigate the components of the QC and ERAD which are required for the degradation of CFTR. Mutants defective in newly discovered components of these processes have enabled testing of their involvement in CFTR degradation. These new experiments reveal that the ubiquitin protein ligases Der3p/Hrd1p and Doa10p seem to have a synergistic effect on the degradation of the CFTR protein. Furthermore the cytosolic trimeric Cdc48-Ufd1-Npl4 complex is found to be crucially required for proteasomal elimination of the protein. In addition the QC and degradation process of CFTR is considerably disturbed in a mutant defective in the ER lumenal lectin Htm1p. Most interestingly this defect can be complemented by the expression of the mammalian EDEM protein, showing that Htm1p and EDEM are functional homologues with respect to CFTR degradation.