There is increasing evidence that T cells are able to control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients, and are limited by numerous immune escape mechanisms of tumor cells selected during immunoediting. An alternative approach to engage T cells for cancer therapy are antibodies, which are bispecific for a surface target antigen on cancer cells, and for CD3 on T cells. These are capable of connecting any kind of cytotoxic T cell to a cancer cell, independently of T-cell receptor specificity, costimulation, or peptide antigen presentation. Here, we review the principle of a new class of bispecific antibodies called BiTE (for “bispecific T-cell engager”) antibodies. Recent results from clinical studies with a CD19/CD3-bispecific BiTE antibody suggest that this therapeutic paradigm is finally showing promise for treatment of both bulky and minimal residual disease. [Cancer Res 2009;69(12):4941–4]