Industrial manufacturing of high-value biopharmaceuticals is dominated by mammalian cells. Advances in mammalian cell engineering have paved the way for remarkable achievements in efficient mammalian cell expression systems; this is crucial for supporting the ever-growing demand for recombinant therapeutic protein products. The emergence of biopharmaceuticals in new formats and limited production capacity of mammalian cells necessitate further improvements of industrial mammalian cell lines, mainly Chinese hamster ovary cells. Next-generation cell engineering platforms are required to overcome these challenges. This chapter describes the current and future cell engineering strategies to achieve high therapeutic protein productivity with desired product quality in biotechnologically important mammalian cell lines.