Export of newly synthesized cargo (ball and stick icons) from the endoplasmic reticulum (ER) to the Golgi occurs through cargo selective budding regions (lower electron micrograph image). The determinants that direct cargo for export are currently thought to be restricted to fully folded, oligomerized cargo through 'quality control' pathways. On page 73 in this issue of Cell, Sekijima et al. explore the relationship between protein folding energetics and secretion. Surprisingly, they demonstrate that protein variants significantly destabilized relative to the wild-type fold are secreted with wild-type efficiency leading to pathological deposits of amyloid fibril aggregates in the extracellular space (upper image depicting blue amyloid aggregates). These observations are used to now frame a new view of the pathways that facilitate cargo flow through ER exit sites. Lower image kindly provided by Dr. G. Palade. (Figure prepared by Mike Pique).