Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation. •Multiplatform-based survey of PI3K/AKT/mTOR across over 10,000 human cancers•Distinct classes of somatic alteration associated with greater pathway activation•Functional interrogation of specific mutations in PIK3CA and PIK3R1•Support for inclusion of IDH1 and VHL mutations within the canonical pathway model Zhang et al. survey the PI3K/AKT/mTOR pathway in >10,000 human cancers across 32 types. In addition to known molecular events, some rare PIK3CA and PIK3R1 mutations activate the pathway, partial copy loss of PTEN or STK11 is associated with poor patient survival, and IDH1 or VHL mutations can confer mTOR activity.