Components of the transforming growth factor-β (TGF-β) signal pathway function as classic tumor suppressors, but the role of the TGF-βs themselves is less clear. Here we show that mice heterozygous for deletion of the TGF-β1 gene express only 10–30% of wild-type TGF-β1 protein levels. Although grossly normal, these mice have a subtly altered proliferative phenotype, with increased cell turnover in the liver and lung. Treatment of these mice with chemical carcinogens resulted in enhanced tumorigenesis when compared with wild-type littermates. However, tumors in the heterozygous mice did not lose the remaining wild-type TGF-β1 allele, indicating that the TGF-β1 ligand is a new form of tumor suppressor that shows true haploid insufficiency in its ability to protect against tumorigenesis.