Large‐scale bioreactors are used for producing biological products (e.g., monoclonal antibodies, fusion proteins, enzymes) expressed in mammalian cells. Compared with small‐scale bioreactors, they are intrinsically more challenging in mixing and mass transfer and require more optimization. Proper bioreactor scale‐up is needed to ensure productivity and product quality. Here, common approaches and challenges in industrial mammalian cell culture scale‐up are covered. These are different from the scale‐up challenges and methodologies typically used in microbial bioreactors, since cell‐culture bioreactors operate in different agitation power and gas flow regimes. Engineering considerations including mass transfer, mixing, and hydrodynamic stress are presented in detail. Single‐use bioreactors are focused due to their rapid adoption by industry in clinical and commercial production. Though the main body of this article is on suspension cultures, special considerations in scaling‐up microcarrier‐based cultures are also briefly discussed. Finally, new challenges and desired improvements in scaling up high density cultures are presented.