Maintenance of hemostasis and pathological thrombus formation are physiological processes inextricably reliant upon intracellular signalling in platelets. The initial tethering of platelets to pro-thrombotic agents exposed at the site of injury triggers molecular events that culminate in activation of the major platelet integrin, αIIbβ3 (“inside-out” signalling). The ensuing conformational change and integrin clustering modulates the affinity of this receptor for its ligands, facilitating stable platelet adhesion and aggregation and triggering integrin αIIbβ3-dependent signalling pathways that control thrombus stability (“outside-in” signalling). Many of the signalling molecules regulating these processes have been elucidated by use of specific inhibitors and knock-out mouse models. However, dissection of this dynamic network is confounded by factors such as the emphasis on different pathways under different conditions and functional redundancies. Furthermore, physiologically, multiple receptors may be simultaneously stimulated and act synergistically to regulate thrombus formation. This review will discuss current concepts in αIIbβ3-mediated signalling in platelets, with a particular focus on the “outside-in” pathways triggered upon αIIbβ3 ligand engagement. Understanding the molecular networks controlling hemostasis and pathological thrombus formation will be important for the development of highly specific therapeutics that can avert disease states without resulting in bleeding diathesis.