Ras activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. We find that PI3Kγ is strongly and directly activated by H-Ras G12V in vivo or by GTPγS-loaded H-Ras in vitro . We have determined a crystal structure of a PI3Kγ/Ras·GMPPNP complex. A critical loop in the Ras binding domain positions Ras so that it uses its switch I and switch II regions to bind PI3Kγ. Mutagenesis shows that interactions with both regions are essential for binding PI3Kγ. Ras also forms a direct contact with the PI3Kγ catalytic domain. These unique Ras/PI3Kγ interactions are likely to be shared by PI3Kα. The complex with Ras shows a change in the PI3K conformation that may represent an allosteric component of Ras activation.