The finding of GTPase inhibiting mutations in genes for alpha subunits of Gs and Gi2 in certain endocrine tumors suggests that heterotrimeric G proteins might contribute to neoplasia. Expression of these activated forms of alpha s or alpha i2 in NIH 3T3 murine fibroblasts induces certain alterations in cell growth, but is weakly transforming. Mutationally activated forms of the alpha subunit of another G protein family, Gq, are fully oncogenic in NIH 3T3 cells, although with a very low potency. In contrast, we have recently shown that overexpression of the alpha subunit of a novel G protein, G12, is itself transforming, and an activated mutant of alpha 12 behaves as one of the most potent oncogenes known. In this study, we have explored whether another member of the G alpha 12 family, G alpha 13, harbors transforming potential. Our data demonstrate that G alpha 13 can behave as a potent dominant acting oncogene. These findings strongly suggest that the G12 family of G proteins represents a novel class of oncogenes.