Adverse immune responses severely hamper the success of biopharmaceutical therapies. Possible clinical consequences include anaphylaxis, reduced drug half-life and neutralization of the therapeutic protein as well as the endogenous human homologue. Controlling potential triggers of the immune system helps to minimize the immunogenicity of biopharmaceuticals, a crucial consideration in biopharmaceutical manufacturing. This review summarizes the latest advancements that have been made towards insight into the impact of structural characteristics on the immunogenicity of therapeutic proteins. Examples are given to illustrate the role of critical quality attributes, such as protein conformation, glycosylation, chemical modifications and aggregation, in immunogenicity. During the development of biopharmaceutical products, it is important to not just assess the risk for immunogenicity in clinical trials, but to ensure product quality throughout drug design, cell-line selection, upstream and downstream processing, all the way to to the final product.