The transformation of a normal cell to one that is malignant can result from mutations in genes that encode proteins with key regulatory functions. Examples include the retinoblastoma gene product (Rb p110), p53, VHL and APC. Using a novel cloning strategy that allows the isolation of previously uncharacterized genes encoding selectable recessive phenotypes, an additional tumor suppressor gene has been identified. This gene, termed tsg 101 for tumor susceptibility gene 101, encodes a stathmin binding domain protein. When expression of this growth inhibitory gene is blocked in NIH/3T3 cells using antisense mRNA, the cells exhibit a transformed phenotype and are tumorigenic in SL6 mice.