Polyclonal antithymocyte globulins (ATGs) are used in organ and allogeneic stem cell transplantation mainly due to their immunomodulatory potential. Since ATGs contain antibodies against antigens expressed on various hematopoetic cells, it is not surprising that they induce cell death not only in healthy T-, B-, NK, and dendritic cells but also in malignant cells of lymphatic and to a lesser extent of myeloid lineage. The cytotoxic and antiproliferative effects of ATGs in malignant B-cells have been known for many years, without attracting clinical attention due to the advent of monoclonal antibodies like rituximab. Recent data indicate a potential role of ATGs in the therapy of multiple myeloma, a disease in which monoclonal serotherapy has been rather unsuccessful. This review discusses available data demonstrating the cytotoxic effects of ATGs and envisages a possible new role of these polyclonal antibodies in the therapy of hematological malignancies.