Upon vessel wall injury platelets rapidly adhere to the exposed subendothelial matrix which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins such as von Willebrand factor, collagen and fibrinogen. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates forming a stable platelet plug. In addition, activated platelets form a strong link between primary and secondary haemostasis as they provide the phospholipid surface that is necessary for the assembly of activated coagulation factor complexes required for thrombin generation. Other than the physiological function acting as a first line of defence against bleeding, platelets may also contribute to pathological thrombus formation. Platelets play an important role in thromboembolic diseases and may contribute to the formation of occlusive thrombi which can lead to severe complications such as stroke or myocardial infarction. Improved understanding of the respective roles of the various cellular receptors, adhesive proteins and regulatory proteins involved in platelet-vessel wall interaction and subsequent thrombus formation, both under physiological and pathological conditions, has led to the development and investigation of a broad range of antiplatelet drugs. This review provides an overview of the current knowledge on the mechanisms involved in the interaction between platelets and vascular endothelium and discusses recent advancements in the development of drugs interfering with platelet-vessel wall interaction at various stages of thrombus formation.