Bispecific antibodies (BsAb) are a new generation of antibody-based therapy, conveying artificial specificity to polyclonal T cells or radiohaptens. These drugs have been successfully implemented to cure hematologic malignancies and are under clinical investigation for solid tumors including HRNB. BsAbs designed to engage T cells or increase the therapeutic index of radiotherapy hold the potential to significantly improve the long-term survival of HRNB patients by shrinking bulky tumors and more effectively eliminating micrometastases and preventing relapse. BsAbs can also be used to arm T cells, yielding a product analogous to CAR T cells, possibly with an improved safety profile. A thoughtful and realistic integration of these therapies into the standard of care should benefit more patients worldwide. Here we describe the history of development of BsAbs for HRNB, which dates back almost three decades. We discuss the merits and pitfalls of all relevant BsAbs, including T cell-engagers and agents used for radioimmunotherapy, highlighting the importance of structural design and interdomain spacing for anti-tumor efficacy.