PIK3CA, the gene for the lipid kinase p110α is one of the most frequently mutated oncogenes across all types of cancer. p110α is an enzyme that catalyzes the formation of phosphatidylinositol 3, 4, 5 Triphosphate (PIP3). PIP3 recruits effector proteins which regulate growth, proliferation and motility. Due to this role as a master cell regulator, the activity of p110α is maintained in an inactive confirmation and is only activated downstream of Receptor Tyrosine Kinases (RTKs) and RAS family of GTPases. p110α is maintained in an inactive confirmation through interactions with its regulatory subunit as well as inhibitory contacts with the C‐terminus. However, oncogenic mutations in p110α breaks these inhibitory interactions and drives hyperactivity without the need for activation signals leading to uncontrolled cell growth. We provide molecular insights into the regulation of oncogenic mutants of p110α using Hydrogen‐Deuterium Exchange Mass Spectrometry (HDX‐MS). HDX‐MS reveals the dynamic changes between the natural cytosolic state and fully‐active membrane bound states of the enzyme. We find unique molecular mechanisms regulating how mutants at the c‐terminus activate lipid kinase activity (H1047R, M1043L, G1049R and N1068KLKR). Using extensive biophysical tools, biochemical assays, and MD simulations, we have tested the oncogenic potential of these mutations. Our results elucidates a unifying theory towards the regulation of PI3Kα and how oncogenic mutations drive hyperactivity. This will aid in understanding the regulation of PI3Kα and in developing isoform specific inhibitors.