PIK3CA mutations activate the PI3K-PTEN-AKT pathway which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. The somatic mutations found thus far in PIK3CA are oncogenic, and the majority of them are clustered within exon 9 and 20 (helical and kinase domains), with three hotspots (E542K, E545K, and H1047R/L). PIK3CA mutations have been reported in various tumor types including up to 36% and 11% of hepatocellular carcinoma and gastric cancer, respectively. They are detected less frequently in cholangiocarcinoma (~6%) and pancreatic adenocarcinoma (~4%). The predictive and prognostic significance of PIK3CA mutations in adenocarcinoma of the small intestine is unclear and needs further elucidation. Clinical trials targeting PI3K/Akt/mTor pathway inhibitors are available for patients with PIK3CA mutated tumors.