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21 p.-9 fig.-2 tab., Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to undergo a large conformational change and interact itself with the membrane in an orientation that places the active site toward the membrane. In this conformation, the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization on the membrane. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and resulting cellular activity including cancer cell invasion, while stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner. Together, our data provide structural details of a key membrane bound state of FAK that is primed for efficient autophosphorylation and activation, hence revealing the critical event in integrin mediated FAK activation and signaling at focal adhesions., I.A. acknowledges support from the José Castillejo Mobility Grant issued by the Spanish Ministry of Education, Culture and Sports. R.D.R. acknowledges funding from the Fellowships for Excellence program sponsored by the Werner-Siemens Foundation and the University of Basel.H.S. acknowledges support by the Swiss National Science Foundation(grants 205320_166164 and 185544 (NCCR TransCure)). M.C.F., A.B., J.C., and C.S. were supported by a Cancer Research UK Programme Grant (C157/ A24837) to M.C.F. F.G. acknowledges funding by the Klaus Tschira Foundation, by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – 2082/1 –390761711, and the state of Baden-Württemberg through bwHPC and the DFG through grant INST 35/11341 FUGG.S.d.B. thanks the Carl Zeiss Foundation for financial support. D.L. acknowledges support from the Spanish Ministry of Economy, Industry and Competitiveness for the Retos Grant BFU2016-77665-R and the Ministry of Science, Innovation and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00,both co-funded by the European Regional Development Fund (FEDER) and from an intramural grant from the Spanish National Research Council(CSIC, Ref: 201820I124). O.L. is funded by SAF2017-82632-P grant from the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI), cofunded by the European Regional Development Fund (ERDF), by the National Institute of Health Carlos III and by projects Y2018/BIO4747 and P2018/NMT4443 from the Autonomous Region of Madrid and co-funded by the European Social Fund and the European Regional Development Fund. C.F.R. is funded by a BES-2015-071348 PhD fellowship by the Spanish Ministry of Science, Innovation and Universities (MCIU/AEI).