CD3 antibodies target the CD3 complex, a group of surface proteins critical for T-cell receptor (TCR) signaling and T-cell activation. Discovered in the late 1970s, the CD3 complex consists of γ, δ, ε, and ζ subunits, forming a TCR-associated module essential for antigen recognition and immune response initiation. CD3 antibodies were initially developed as research tools to study T-cell biology, leveraging their ability to modulate TCR signaling. Clinically, the first therapeutic CD3 antibody, OKT3 (muromonab), approved in the 1980s, revolutionized organ transplantation by suppressing T-cell-mediated graft rejection. However, its use declined due to severe cytokine release syndrome (CRS). Modern CD3 antibodies, often engineered to reduce Fc receptor binding, minimize side effects while retaining immunosuppressive or activating properties. They are now explored in autoimmune diseases (e.g., teplizumab for type 1 diabetes) and cancer immunotherapy, particularly bispecific T-cell engagers (BiTEs) like blinatumomab, which links CD3 to tumor antigens to redirect T cells against malignancies. Ongoing research focuses on optimizing CD3-targeting agents for precision, safety, and broader therapeutic applications.