Platelet activation is crucial for normal hemostasis to arrest bleeding following vascular injury. However, excessive platelet activation in narrowed atherosclerotic blood vessels that are subject to high shear forces may initiate the onset of arterial thrombosis. When platelets come into contact with, and adhere to collagen exposed by damaged endothelium, they undergo morphological and functional changes necessary to generate a platelet-rich thrombus. This process is complex and involves precise co-ordination of various signaling pathways which lead to firm platelet adhesion to sites of tissue damage, release of granule contents from activated platelets, platelet shape change, platelet aggregation and subsequent thrombus formation and consolidation. Induction of tyrosine phosphorylation of key signaling molecules has emerged as a critical event central to stimulatory signaling pathways that generate platelet activation, but is an essential component associated with regulatory pathways that limit the extent of platelet activation. Understanding mechanisms that regulate platelet activation may contribute to the development of novel therapeutics that control common vascular diseases such as myocardial infarction and ischaemic stroke.