The prostate is a highly androgen-dependent tissue that in humans exhibits marked susceptibility to carcinogenesis. The malignant epithelium generated from this tissue ultimately loses dependence on androgens despite retention or amplification of the androgen receptor. Accumulating evidence support that transforming growth factor-beta (TGF-beta) plays key roles in the control of androgen dependence and acquisition of resistance to such hormonal control. Although TGF-beta functions as a key tumour suppressor of the prostate, it can also promote malignant progression and metastasis of the advanced disease, through undefined mechanisms. In addition to giving an overview of the TGF-beta field as related to its function in prostate cancer, this Review focuses on novel findings that support the tumour suppressor function of TGF-beta is lost or altered by changes in the activity of the androgen receptor, insulin-like growth factor-I, Akt, and mTOR during malignant progression. Understanding the mechanisms of cross-talk between TGF-beta and such growth modulators has important implications for the rational therapeutics of prostate cancer.