Monoclonal antibodies (mAbs) have become established as targeted therapies for various diseases, including malignancies, transplant rejection, autoimmune, and infectious diseases. However, their administration carries risks such as immune reactions, including acute anaphylaxis, serum sickness, and the generation of antibodies. Additionally, mAbs can cause adverse effects related to their specific targets, such as infections, cancer, autoimmune diseases, and organ-specific events like cardiotoxicity. The review discusses the adverse effects encountered with mAb therapies and advances in preclinical testing and antibody technology aimed at minimizing these risks. It highlights the importance of understanding the mechanisms of action and developing strategies to reduce the likelihood of severe adverse events, such as cytokine release syndrome (CRS), which was observed in the first-in-human study of TGN1412, a CD28-specific superagonist mAb. The article also covers the development of mAbs, from mouse to chimeric, humanized, and fully human forms, and the regulatory actions taken to ensure safety. Finally, it emphasizes the need for improved preclinical testing and communication between scientists, clinicians, and regulatory bodies to enhance the safety of mAb-based therapies.Monoclonal antibodies (mAbs) have become established as targeted therapies for various diseases, including malignancies, transplant rejection, autoimmune, and infectious diseases. However, their administration carries risks such as immune reactions, including acute anaphylaxis, serum sickness, and the generation of antibodies. Additionally, mAbs can cause adverse effects related to their specific targets, such as infections, cancer, autoimmune diseases, and organ-specific events like cardiotoxicity. The review discusses the adverse effects encountered with mAb therapies and advances in preclinical testing and antibody technology aimed at minimizing these risks. It highlights the importance of understanding the mechanisms of action and developing strategies to reduce the likelihood of severe adverse events, such as cytokine release syndrome (CRS), which was observed in the first-in-human study of TGN1412, a CD28-specific superagonist mAb. The article also covers the development of mAbs, from mouse to chimeric, humanized, and fully human forms, and the regulatory actions taken to ensure safety. Finally, it emphasizes the need for improved preclinical testing and communication between scientists, clinicians, and regulatory bodies to enhance the safety of mAb-based therapies.