Many factors influence the immunogenicity of protein-based therapeutics. At present, it is inconceivable to manufacture a biopharmaceutical without the risk of this adverse effect. Thus, the detection and characterization of antibodies against protein-based therapeutics is a significant task. Only clinical studies and careful monitoring of the market can be used to conclusively demonstrate rates of immunogenicity in humans for protein therapeutics. Fully validated, reliable, and robust in vitro assays, in combination with sensitive bioassays, should be used to address these topics.