Recent studies have shown that the gip2 and gep oncogenes defined by the α-subunits of Gi2 and G12 family of G proteins, namely Gαi2 and Gα12/13, stimulate oncogenic signaling pathways in cancer cells including those derived from ovarian cancer. However, the critical α-subunit involved in ovarian cancer growth and progression in vivo remains to be identified. Using SKOV3 cells in which the expressions of individual Gα-subunits were silenced, we demonstrate that the silencing of Gα12 and Gα13 drastically attenuated serum- or lysophosphatidic acid-stimulated proliferation. In contrast, the invasive migration of these cells were reduced only by the silencing of Gαi2 or Gα13. Analyses of the xenograft tumors derived from these Gα-silenced cells indicated that only the silencing of Gα13 drastically reduced xenograft tumor growth and prolonged the survival of the mice. Similar, but albeit reduced, effect was seen with the silencing of Gα12. On the contrary, the silencing of Gαi2 or Gαq failed to exert such effect. Thus, our studies establish for the first time that Gα12/13, the putative gep oncogenes, are the determinant α-subunits involved in ovarian cancer growth in vivo and their increased oncogenicity can be correlated with its ability to stimulate both proliferation and invasive migration.