During sepsis and inflammation profound changes in physiological function are induced by a variety of mediators, including endotoxin, various cytokines, and NO. Many of these mediators, in addition to their other functions, induce the synthesis of NO through the induction of iNOS within a variety of cell types. The regulation of iNOS expression is quite complex. Of interest is the fact that the functions of NO during sepsis range from modulating perfusion to mediating cytotoxicity. In addition, it is unique that many tissues not characterized as being involved in immune function express iNOS in a manner similar to that of tissues involved in immune function. The role of NO during episodes of acute inflammation appears to be a protective one; however, there are examples of chronic localized inflammation in both animal and human models which suggest that chronic iNOS expression may be detrimental. Further investigations into the regulation and function of NO in both the acute and chronic settings are necessary in order to fully understand this small yet unique molecule.