Nitric oxide (NOи) is an arginine-derived nitrogenbased radical that is rapidly becoming one of the most important molecular species to be discovered. Over the past decade, an explosion of evidence has revealed the extreme complexity of function of this seemingly simple inorganic molecule. It is now evident that NOи demonstrates a functional dualism, playing a pivotal role in numerous physiologic and pathophysiologic processes. Whether this molecule is beneficial or detrimental is dependent upon the tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, and the presence or absence of NOи transduction elements. Nitric oxide is generated by three independent isoenzymes that resemble the p-450 enzyme superfamily in both form and function. It ultimately alters enzymatic function through covalent modification, redox interactions, and interactions with metallic functional centers. This radical is a key figure in a number of pathophysiologic processes by means of similar yet uncoordinated interactions. In consideration of the already broad spectrum of roles attributed to NOи, it seems highly likely that this molecule will be implicated in an ever widening variety of functions relative to the practice of otolaryngology-head and neck surgery. This article reviews the enzymology, signal transduction mechanisms, physiology, and pathophysiology of NOи as it pertains to head and neck cancer.