Functional responses to Nitric Oxide (NO) are changed in the vasculature in response to hypertension, diabetes and atherosclerosis. This is most clearly manifested in a decreased vasorelaxation in response to endothelial-derived NO which arises as a consequence of the failure to activate the cGMP -dependent pathways which lead to decreased intracellular Ca2+. This appears to be due to a) the down regulation of the cGMP -dependent protein kinase G in vascular smooth muscle and b) the production by the endothelium of the free radical superoxide which reacts with NO to form peroxynitrite. The focus of this talk will be how these interactions change the response of the vasculature in atherosclerosis through the interplay of peroxynitrite and NO -dependent signalling pathways.