This commentary proposes the working hypothesis that transforming growth factor-beta (TGF-beta) can play two different and opposite roles with respect to the process of malignant progression. During the earliest stages of carcinogenesis, TGF-beta can act as potent tumor suppressor and may mediate the actions of chemopreventive agents such as retinoids and tamoxifen. However, at some point during the development and progression of malignant neoplasms, bioactive TGF-betas make their appearance in the tumor microenvironment and the tumor cells appear to escape from TGF-beta-dependent growth arrest. Evidence is accumulating rapidly that this TGF-beta resistance is the consequence of inactivating mutations in any one of the genes that encode signaling intermediates, which include the type I and type II TGF-beta receptors, as well as several Smad proteins. The potential implications of the phenotypic switch from TGF-beta sensitive to TGF-beta resistance that occurs during carcinogenesis for cancer prevention and treatment are discussed.