The mechanistic basis for quality control surveillance within the secretory pathway remains poorly understood. We have used a systematic approach to discover proteins that influence the biogenesis of a model misfolded protein, the yeast ABC transporter, Yor1. Broadly analogous to human CFTR, mutations in which cause cystic fibrosis, Yor1 acts at the plasma membrane as a drug pump to confer resistance to oligomycin. Misfolding mutations cause ER retention and proteasomal degradation, leading to oligomycin sensitivity. This phenotype affords a rapid and robust screen for mutations that enhance or suppress the ability of cells to tolerate increasing concentrations of drug. Using a high throughput genetic screen, we measured the effect of each non-essential yeast gene on growth conferred by Yor1-∆F, equivalent to the predominant disease-causing allele in CFTR. We discovered novel regulators of membrane protein biogenesis, including a pathway that seems to detect protein misfolding at the earliest stages of protein synthesis. We propose misfolding events can generate feedback to the ribosome that halts or slows translation, serving to either promote folding or prevent aberrant proteins from entering the secretory pathway. We also discovered an unexpected role for an ER export receptor, Erv14, which seems to increase the affinity of cargo proteins for the vesicle coat proteins, thereby enhancing ER egress. Genetic and physical interactions between the various regulators we identified suggest that these events are coordinated to promote efficient protein synthesis, folding and forward traffic.