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Publisher Summary This chapter summarizes the molecular mechanisms that govern inducible nitric oxide synthase (iNOS) gene expression, focusing on the regulation of iNOS transcription. The gene for iNOS is expressed by many species and in a large variety of cell types. Typically, the expression is repressed in resting cells, requiring activation by an expanding number of biological, chemical, or physical stimuli. The molecular regulation of iNOS expression is complex and occurs at multiple sites in the gene expression pathway, with both transcriptional and posttranscriptional control mechanisms. Induction of nitric oxide synthesis has been shown to elicit either beneficial or detrimental consequences depending on the physiological or pathophysiological condition. An understanding of the signaling pathways and molecular mechanisms that regulate iNOS expression is critical for the development of effective therapies to modulate its expression in disease states. The major differences between human and rodent gene regulation as well as the mechanisms that downregulate iNOS expression are highlighted.