Monoclonal antibodies (mAbs) have transformed therapeutic strategies for various diseases. Their high specificity to target antigens makes them ideal therapeutic agents for certain diseases. However, a challenge to their application in clinical practice is their potential risk to induce unwanted immune response, termed immunogenicity. This challenge drives the continued efforts to deimmunize these protein therapeutics while maintaining their pharmacokinetic properties and therapeutic efficacy. Because mAbs hold a central position in therapeutic strategies against an array of diseases, the importance of conducting comprehensive immunogenicity risk assessment during the drug development process cannot be overstated. Such assessment necessitates the employment of in silico, in vitro, and in vivo strategies to evaluate the immunogenicity risk of mAbs. Understanding the intricacies of the mechanisms that drive mAb immunogenicity is crucial to improving their therapeutic efficacy and safety and developing the most effective strategies to determine and mitigate their immunogenic risk. This review highlights recent advances in immunogenicity prediction strategies, with a focus on protein engineering strategies used throughout development to reduce immunogenicity.