Mammalian cells play a dominant role in the industrial production of biopharmaceutical proteins. However, the productivity of producer cells is often hindered by a bottleneck in the saturated secretory pathway, where a sophisticated mechanism of vesicle trafficking is mediated by numerous proteins and their complexes, among which are the cross-kingdom conserved SNAREs [soluble NSF (N-ethylmaleimide-sensitive factor) receptor]. The SNAREs assemble into complexes by means of four interactive alpha-helices and, thus, trigger the fusion of transport vesicles with the respective target membranes. We report that the transgenic expression of exocytic SNAREs, which control the fusion of secretory vesicles to the plasma membrane, differentially impacts the secretory capacity of HEK-293, HeLa, and CHO-K1 cells. While other exocytic SNAREs have no effect or a negative effect, SNAP-23 [synaptosome-associated protein of 23 kDa] and VAMP8 [vesicle-associated membrane protein 8] specifically increase the production of recombinant proteins when they are ectopically and stably expressed in mammalian cells. The targeted and effective intervention in the secretory capacity of SNARE proteins is a novel engineering strategy, which could lead to the development of new therapies by increasing the production of biopharmaceutical proteins or by boosting the secretion of cell implants in cell therapy initiatives. Biotechnol. Bioeng. 2011; 108: 611-620. (C) 2010 Wiley Periodicals, Inc.