Biologic drug development is a rapidly evolving sector in the biopharmaceutical industry. Although the success of biologics has been demonstrated, there are inherent operational and technological challenges associated with this complex class of drugs. One of these challenges—immunogenicity—has become a key area of regulatory interaction. Immunogenicity (IG) is defined by the FDA as the propensity of the therapeutic protein to generate immune responses to itself and to related proteins, or to induce immunologically-related adverse clinical events. A quantitative systems pharmacology (QSP) based approach can be used to predict and better manage immunogenicity, and as a tool to guide clinical and regulatory decision-making in biologics drug development.