Bioprocess optimization has yielded powerful clones for biotherapeutic production. However, new genomic technologies allow more targeted approaches to cell line development. Here we review efforts to enhance protein production in mammalian cells through metabolic engineering. Most efforts aimed to reduce toxic byproducts accumulation to enhance protein productivity. However, recent work highlights the possibility of regulating other desirable traits (e.g., apoptosis and glycosylation) by targeting central metabolism since these processes are interconnected. Therefore, as we further detail the pathways underlying cell growth and protein production and deploy diverse algorithms for their analysis, opportunities will arise to move beyond simple cell line designs and facilitate cell engineering strategies with complex combinations of genes that together underlie a phenotype of interest.