The annual demand for therapeutic human serum albumin (HSA) is estimated to be more than 500 metric tons worldwide. As a major protein in the human body, HSA plays a vital role in many physiological processes, including the maintenance of oncotic pressure and the transportation of various biomolecules and pharmaceuticals. Currently, all HSA used for clinical blood expansion purposes is isolated from pooled human blood or plasma, an unpredictably fluctuating supply that can at times fall to dangerously low levels. Furthermore, this supply is derived from thousands of different donors and can potentially result in the spread of pathogenic contaminants to recipients. The use of transgenic animals, such as cattle, as living bioreactors, provides a potential solution to this problem by... enabling the large-scale production of recombinant HSA (rHSA) in a cost-effective manner. Cattle are capable of producing large amounts of milk that can potentially yield abundant quantities of a desired recombinant protein. The production of rHSA in the milk of cattle would provide an economical resource that circumvents the current dependence on blood-derived sources. One challenge to this system, however, is the presence of endogenous bovine serum albumin (BSA) in the milk. BSA is a highly conserved ortholog of HSA that necessitates a tedious and prohibitively expensive purification process, which has up to now hindered the efficient purification of rHSA from bovine milk. Here we overview our approach to humanize the endogenous BSA gene, replacing it with an rHSA minigene construct, which should allow for normal expression of rHSA protein in the liver, as well as exogenous expression of rHSA in the milk. The future generation of such cattle supports the potential for a safer and more reliable source of therapeutic rHSA.