Transforming growth factor-beta (TGF-beta) is a potent regulator of numerous processes including hematopoiesis, cell proliferation, differentiation and activation. TGF-beta has pleiotropic and profound effects on the immune system and on hematologic malignancies, ie leukemia. It is the most potent immunosuppressor described to date. Evidence exists that the immunosuppressive potential of TGF-beta is an important promoter of malignant cell growth. This is partly caused by TGF-beta-induced interference with the generation of tumor-specific cytotoxic T lymphocytes, but also by TGF-beta-induced promotion of angiogenesis and tumor stroma formation. Until now, significant clinical responses have not been achieved with the current cancer immunotherapeutic approaches. One of the possible explanations for this failure is immunosuppression induced by tumor-derived TGF-beta. Here, several strategies to counteract the immunosuppressive effects of TGF-beta and the current limitations of these strategies will be discussed. Knowledge of the mechanisms by which TGF-beta interferes with the development of an anti-tumor response and of the strategies to counteract these immunosuppressive activities is crucial to improve the current cancer immunotherapeutic approaches.