Myriad choices confront manufacturers before they even consider optimizing downstream processes. Each decision directly influences what final options will be available on arriving at the final stages of downstream processing and then interlock with fill/finish steps, which demand still more evaluation and forethought. Biopharmaceutical expression systems range from yeast and insects to mammals and plants. Bioreactors to house these systems might be stirred-tank, air-lift, fixed-bed, hollow-fiber perfusion, or suspension, perhaps even hybrid combinations thereof. All of these lead to a gamut of membrane separation, centrifugation, extraction, precipitation, and chromatography technologies. Biology and financial costs then ultimately dictate what works best for each company’s, institute’s, or organization’s reach and ambition.