The response of platelets to changes in the immediate environment is always a balance between activatory and inhibitory signals, the cumulative effect of which is either activation or quiescence. This is true of platelets in free flowing blood and of their regulation of haemostasis and thrombosis. In this review, we consider the endogenous inhibitory mechanisms that combine to regulate platelet activation. These include those derived from the endothelium (nitric oxide, prostacyclin, CD39), inhibitory receptors on the surface of platelets (platelet endothelial cell adhesion molecule-1, carcinoembryonic antigen cell adhesion molecule 1, G6b-B - including evidence for the role of Ig-ITIM superfamily members in the negative regulation of ITAM-associated GPVI platelet-collagen interactions and GPCR-mediated signalling and in positive regulation of "outside-in" integrin α(IIb)β(3)-mediated signalling), intracellular inhibitory receptors (retinoic X receptor, glucocorticoid receptor, peroxisome proliferator-activated receptors, liver X receptor), and emerging inhibitory pathways (canonical Wnt signalling, Semaphorin 3A, endothelial cell specific adhesion molecule, and junctional adhesion molecule-A).