Transforming growth factor-beta (TGF-beta) induces cell differentiation and suppresses cell proliferation, but the mechanisms underlying the actions of TGF-beta remain to be fully elucidated. Recent studies suggest that TGF-beta suppresses neoplastic cell development by employing Smad3 protein to repress the gene of human telomerase reverse transcriptase (hTERT). In human breast cancer cells, TGF-beta induces rapid phosphorylation and subsequent entry of Smad3 into the nucleus. In the nucleus, Smad3 binds to the hTERT gene promoter directly and inhibits hTERT gene transcription activity. By interacting with c-myc, Smad3 also represses the c-myc gene. Thus, TGF-beta prevents continuous cell proliferation by switching off telomerase activity through Smad3 repression of the hTERT gene and the action of c-myc. Modulating the interface between Smad3 and the hTERT gene, and the potential feedback loop from telomeres to Smad3 via Smurf2, may represent a novel approach to regulate cell lifespan of proliferation.