Nitric oxide (NO) has been proposed to be a key molecule in migraine. Experimental evidence suggests its intervention in vasodilatation and activation of the trigeminovascular system as well as its involvement in the supraspinal pathways implicated in head and pain processing. Other findings suggest the implication of NO in coupling neuronal and vascular changes during spreading depression. A potential role for NO has also been proposed in the pathophysiological mechanisms underlying cluster headache and chronic tension-type headache. The most relevant evidence for an increased response to exogenous NO in all primary headaches emerges from the experimental model of nitroglycerin-induced headache. Moreover, the effectiveness of non-selective NO synthase inhibitor L-N-monomethylarginine (L-NMMA) further supports the involvement of NO in migraine and chronic tension-type headache. The endogenous increase in NO production has been shown only in studies carried out during spontaneous migraine attacks which demonstrated increased levels of nitrites and cGMP in peripheral blood and internal jugular blood; the latter was followed by an increased production of algogenic and vasodilatatory prostanoids. These data suggest the potential activation of cyclooxygenase (COX) due to NO. Additional evidence suggests the increased activity of L-arginine/NO pathway in the platelet model in migraine patients. This increase was also evident between attacks, more accentuated during attacks and expressed to a greater extent during late luteal phase in menstrual migraine. Higher NO production in platelet was also demonstrated in patients affected by chronic daily headache and they are accompanied by significant lower serotonin content and higher levels of intracellular calcium. Whether these changes may be expressed in the central nervous system is a matter of discussion. These data taken together suggest a crucial role played by NO in neurovascular headaches and chronic headaches. Further research concerning NO in all primary headaches will be aimed at verifying changes of reliable markers of NO metabolism and NO effects, to better understand the complex COX/NO synthase (NOS) interactions, to investigate the effectiveness of selective NOS inhibitors in discriminating neural versus vascular involvement of NO.