Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations. Display omitted •PIK3CA mutations and/or PTEN aberrations are frequent in diverse advanced cancers•Testing for PIK3CA and PTEN aberrations can predict benefit of PI3K/mTOR inhibitors•Results further support accelerated use of biomarker-driven trials in cancer Despite a wealth of preclinical studies, it is unclear whether PIK3CA or PTEN gene aberrations are actionable in the clinical setting. Janku and colleagues show that, even in patients with advanced refractory tumors, treatment with PI3K/AKT/mTOR axis inhibitors can produce significant responses and that these responses are observed across multiple histologies. Furthermore, patients whose tumors harbor an H1047R PIK3CA mutation may do especially well when cognate inhibitors are given. This work has important implications for clinical management.