Transforming growth factor-beta (TGF-beta) is a key player in malignant disease through its actions on host tissues and cells. Malignant cells often secrete large amounts of TGF-beta that act on nontransformed cells present in the tumor mass as well as distal cells in the host to suppress antitumor immune responses creating an environment of immune tolerance, augmenting angiogenesis, invasion and metastasis, and increasing tumor extracellular matrix deposition. Cells of the innate immune system contribute to the high concentrations of TGF-beta found in tumor masses. In addition, dendritic cell subpopulations secreting TGF-beta contribute to the generation of regulatory T cells that actively inhibit the activity of other T cells. Elevated levels of plasma TGF-beta are associated with advanced stage disease and may separate patients into prognostically high-risk populations. Anti-TGF-beta therapy could reverse the immunosuppressive effects of this cytokine on the host as well as decrease extracellular matrix formation, decrease angiogenesis, decrease osteolytic activity, and increase the sensitivity of the malignant cells to cytotoxic therapies and immunotherapies. Phase I clinical trials of an inhibitor of TGF-beta receptor type I kinase activity and a TGF-beta neutralizing antibody are under way.