During sepsis and inflammation profound changes in physiological function are induced by a variety of mediators, including endotoxin, various cytokines, eicosanoids, and NO. It has been established that nitric oxide (NO) plays an important role as one of these mediators, in addition to its functions in cell–cell communications and neurotransmission. As the product of three distinct isoforms of NO synthases, it is the inducible isoform (iNOS), which is expressed by a wide variety of cell types in response to stimulation, producing much larger quantities of NO relative to the two other isoforms, which is the predominant isoform active during sepsis and inflammation. Cell types that express iNOS in response to stimulation by certain cytokines and microbial products include hepatocytes, macrophages, Kupffer's cells, and chondrocytes. The regulation of iNOS expression is quite complex, as it involves a variety of mechanisms within a wide range of cell types. For example, the factors that have been found to be important in the rodent for regulating iNOS expression within hepatocytes, as compared with nonhepatocytes, include transcriptional and posttranscriptional as well as posttranslational mechanisms. Adding to this complexity, both beneficial and deleterious effects have been attributed to iNOS expression. This chapter reviews the regulation and function of iNOS expression during sepsis and inflammation and discusses the implications of NOS inhibitors.