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Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (Pl3K alpha) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased P13K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110 alpha binding to the inhibitory subunit p85 alpha, which relieves its catalytic inhibition, and increased p110 alpha membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3K alpha inhibitors compared with single-hotspot mutations.