Improvements in the productivity of established mammalian cell lines used for biopharmaceutical production are desirable to increase product yields. Chinese hamster ovary (CHO) cells are the workhorse used for more than 60% of industrial therapeutic antibody production. Glycoprotein secretion by CHO cells requires intracellular processes including transcription, translation, glycosylation, and secretion. Within these intracellular steps, post-translational processes are rate limiting for production in high-producer cell lines. This review focuses on unfolded protein response-based engineering of CHO cells and details our recent progress in using overexpression of activating transcription factor 4 to promote recombinant protein production.