A large fraction of the proteome is synthesized and folded in the endoplasmic reticulum (ER), a multifunctional compartment also playing pivotal roles in Ca(2+) storage, redox homeostasis and signalling. From the ER, secretory proteins begin their journey towards their final destinations, the organelles of the exocytic and endocytic compartments, the plasma membrane or the extracellular space. Fidelity of protein-based intracellular communication is guaranteed by quality control (QC) mechanisms located at the ER-Golgi interface, which restrict forward transport to native proteins. QC is used also to time or shape the secretome. Furthermore, professional secretory cells face a problem of quantity, as well as quality of their protein products. This essay summarizes recent findings that identify ERp44 as a key regulator of protein secretion, Ca(2+) signalling and redox regulation. © 2010 Blackwell Publishing Ltd.