In healthy blood vessels excessive platelet activation is counterbalanced by negative signalling cascades that modulate activation. This is achieved primarily through endothelial-derived nitric oxide (NO) and prostacyclin (PGI2). The biological effects of NO are mediated through stimulation soluble guanylyl cyclase (sGC) activation of cyclic AMP and GMP-mediated signalling pathways. In the present review examine our current understanding of NO-mediated regulation of platelets and highlight key issues that remain unresolved.