CPY* is a mutated and malfolded secretory enzyme (carboxypeptidase yscY, Gly255Arg), which is imported into the endoplasmic reticulum but never reaches the vacuole, the destination of its wild type counterpart. Its creation, through mutation, had a major impact on the elucidation of the mechanisms of quality control and associated protein degradation of the endoplasmic reticulum, the eukaryotic organelle, where secretory proteins start the passage to their site of action. The use of CPY* and yeast genetics led to the discovery of a new cellular principle, the retrograde transport of lumenal malfolded proteins across the ER membrane back to their site of synthesis, the cytoplasm. These tools furthermore paved the way for our current understanding of the basic mechanism of malfolded protein discovery in the ER and their ubiquitin-proteasome driven elimination in the cytosol (ERQD).