Fire sweeps through the brush. In its aftermath, dormant seeds of chaparral, savanna, heath, and scrub begin to germinate in response to a “go” signal in the smoke. Even though smokesoaked water kills the seeds, in diluted form it triggers their development. The chemical cues are nitrogen oxides (1). This lesson of death and life in the field mirrors comparable events within us, where reactive nitrogen intermediates (RNI) 1 deliver both death-and life-promoting messages. As described in Michel and Feron’s introduction to this series (2), RNI include not only nitric oxide (NO), the primary reactive product of nitric oxide synthases (NOSs), but also those species resulting from NO’s rapid oxidation, reduction, or adduction in physiologic milieus, such as NO2, NO2, N2O3, N2O4, S-nitrosothiols, and peroxynitrite (OONO). In mammals, there is a rough correspondence between toxic and homeostatic functions of NO and its production in large and small quantities, respectively.

The high-output path of NO production is the hallmark of the second isoform of NOS to be cloned, NOS2. NOS2 was named “iNOS”(3) to connote its independence of elevated intracellular Ca2, the distinguishing biochemical feature primarily responsible for conferring the capacity of this isoform for more sustained catalysis than typically exercised either by nNOS (NOS1) or eNOS (NOS3)(4). Because iNOS is expressed in most cells only after induction by immunologic and inflammatory stimuli, the “i” doubles for “inducible.” 5 yr after mouse iNOS cDNA was cloned (3, 5, 6), and 2 yr after the NOS2 gene was disrupted in mice through homologous recombination (7–9), it is timely to take stock: What does iNOS contribute to mammalian pathophysiology? The complexity of this question has elicited multiple responses addressed to different facets of an answer (eg, references 10–15). The approach of this Perspective is to focus on lessons emerging from