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Transforming growth factor–β (TGF-β) inhibits cell proliferation, and acquisition of TGF-β resistance has been linked to tumorigenesis. A genetic screen was performed to identify complementary DNAs that abrogated TGF-β sensitivity in mink lung epithelial cells. Ectopic expression of murine double minute 2 rescued TGF-β–induced growth arrest in a p53-independent manner by interference with retinoblastoma susceptibility gene product (Rb)/E2F function. In human breast tumor cells, increased MDM2 expression levels correlated with TGF-β resistance. Thus, MDM2 may confer TGF-β resistance in a subset of tumors and may promote tumorigenesis by interference with two independent tumor suppressors, p53 and Rb.