The increase in quality, quantity, and complexity of recombinant products relies heavily on the ability to engineer mammalian cell systems. However, the complexity of mammalian cells and lack of synthetic tools to manipulate them impede cell line development processes. Furthermore, the issues of cell productivity, cell stability, cost of goods and services, and speed of development have put new demands on the field. Synthetic biology tools, which have long been applied to microbial cell systems, can improve the speed of R&D and reduce cost of goods. This review highlights recent advances in site-specific genome editing techniques, genetic regulatory elements, and metabolic and pathway engineering of mammalian cell systems that can ultimately facilitate faster and more flexible cell line development.