If there is one serious patient safety concern that permeates every aspect of biopharmaceutical manufacturing, it is the ever-present threat of introducing and then further propagating adventitious agent contamination. Adventitious agents can enter into the manufacturing process through raw materials, starting materials, and operation of the upstream cell/seed culture manufacturing steps; but also, even the operation of the downstream and drug product manufacturing process steps. Because biopharmaceutical manufacture is linked to living systems, if adventitious agents are introduced into the biological process, they have the potential of being propagated and causing even greater patient harm. In this chapter, the four primary adventitious agents of concern for biopharmaceuticals are examined in detail—prions, viruses, mycoplasmas, and bacteria/fungi. The various complementary risk mitigating approaches for controlling for these contaminating agents are discussed. The strength of each risk mitigating approach varies between the protein-based biopharmaceutical processes (recombinant proteins and monoclonal antibodies) and the gene-based biopharmaceutical processes (viral vectors, non-viral vectors, and genetically modified patient cells). Where it may be appropriate to use a risk-based minimum CMC regulatory compliance continuum approach in controlling for adventitious agent contamination is also considered. While each manufacturing process type has a different level of risk due to adventitious agent contamination, there is no biopharmaceutical manufacturing process that carries no risk of adventitious agent contamination.