Homeostasis of the protein folding machinery in the endoplasmic reticulum (ER) is maintained via several parallel unfolded protein response pathways that are remarkably conserved from yeast to man. Together, these pathways are integrated into a complex circuitry that can be modulated in various ways, not only to cope with various stress conditions, but also to fine-tune the capacity of the ER folding machinery when precursor cells differentiate into professional secretory cells.