Generation of functional recombinant proteins requires efficient and undisturbed functioning of the ER-Golgi secretory pathway in host cells. In large-scale production, where target proteins are highly overexpressed, this pathway can be easily congested with unfolded or misfolded proteins. Accumulating evidence suggests that, in addition to responsibility for protein processing, ER is also an important signaling compartment and a sensor of cellular stress. Two ER responses have been described to arise from the overaccumulation of proteins: unfolded protein response (UPR) and ER overload response (EOR). UPR and EOR employ various mechanisms at the transcriptional and the translational levels to deal efficiently and appropriately with encountered stress. This review will outline the molecular bases of ER functioning and stress response, highlight the relevance of ER signaling to the large-scale cell culture productivity and discuss possible approaches to the improvement of the secretion capacities of recombinant cells.