The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation. It has recently been reported that somatic mutations within the PI3K subunit p110? (PIK3CA) are present in human colorectal and other cancers. Here we show that thirteen of fifty-three breast cancers (25%) contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain. These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis.