Rat nerve growth factor receptor ectodomain (NGFRe) and Escherichia coli beta-lactamase were translocated into the yeast endoplasmic reticulum (ER), glycosylated, misfolded and rapidly degraded. NGFRe underwent ATP-dependent thermosensitive degradation independently of vesicular transport. Since no evidence for degradation by the cytoplasmic 26S proteosome complex could be obtained, NGFRe appeared to be degraded in the ER. Beta-lactamase exited the ER by vesicular traffic and was transported from the Golgi via the Vps10 receptor pathway to the vacuole for degradation. Machineries in the ER and the Golgi appear to recognize distinct structural features on misfolded heterologous proteins and guide them to different degradation pathways.