Integrins have a critical role in thrombosis and haemostasis(1). Antagonists of the platelet integrin alpha(IIb)beta(3) are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding(2,3). It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally(4,5). Inside-out signalling activates integrins through a talin-dependent mechanism(6,7). Integrin ligation mediates thrombus formation and outside-in signalling(8,9), which requires G alpha(13) and greatly expands thrombi. Here we show that G alpha(13) and talin bind to mutually exclusive but distinct sites within the integrin beta(3) cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and G alpha(13) binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of G alpha(13)-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.