Members of the transforming growth factor-beta family, especially transforming growth factor-beta type 1, are among the most potent growth-inhibitory factors for epithelial, lymphohematopoietic, and neuroectodermal cells. Resistance to transforming growth factor-beta-mediated growth inhibition is frequently observed in cancers derived from these cell types. We review two important aspects of cancer cell resistance to transforming growth factor-beta: 1) It occurs progressively during the multistep process of tumor progression, and 2) it may encompass a potentially wide range of mechanisms involving transforming growth factor-beta-receptor alterations and cell-signaling defects. Stepwise increases in resistance to the growth-inhibitory action of transforming growth factor-beta may therefore sometimes be attributed to not one but several defects that are involved in transforming growth factor-beta activation, binding, and signaling. These factors accumulate within expanding tumor subclones during disease progression.