Immunogenicity testing is crucial because the protein-based therapeutics, such as monoclonal antibodies and vaccines, are sometimes recognized as foreign particles by the body and induce an unwanted immunogenic response. Thus, immunogenicity assessment of biologics or therapeutic proteins is mandatory for regulatory approval. Often immune response involves B or T cell epitopes. For immunogenicity prediction, histocompatibility complex class II/ MHC is identified as an immunogenic molecule that shows T-epitopes as the receptors for cascade responses. These types of cells are responsible for producing antibodies and inactivating the administered protein-based drugs. Other risk factors for immunogenicity testing include dosage, administration route, delivery vehicle, and immune system activation to predict the immunogenicity of protein. Thus, measuring the capacity of producing antibodies is an essential aspect for the safety of clinical trials and for the success of therapeutic drugs. Immune tolerance can also significantly affect the therapeutics product design in many cases. Rheumatoid Arthritis and Hemophilia A exemplify health conditions that have complicated treatments due to immunogenicity.