Nitric oxide (NO˙) is a pleiotropic biological messenger mediating important functions such as neurotransmission and control of blood pressure, blood flow, thrombocyte aggregation and growth of tumor cells and intracellular pathogens. Upon induction by selected cytokines or bacterial constituents, Mø synthesis de novo inducible nitric oxide synthase (iNOS) which promotes the synthesis of large amounts of NO˙ over hours or days. This high NO˙output may be beneficial to the host, or may yield pathological sequelae, depending on the circumstances. Pathological consequences include induction of apoptosis, protein modification, DNA damage, immunosuppression, neuronal dysregulation, and inhibition of respiration, protein synthesis and hematopoiesis. This may explain why iNOS induction in Mø is under tight transcriptional and posttranscriptional control. This review emphasizes the variation in iNOS regulation observed in Mø from different species, in different cells within one species and highlights differences in iNOS expression between cells of lesions in vivo and of cultured cells. It shows that the well-known species differences in iNOS inducibility between murine and human Mø is paralleled by similar differences between cultured Mø from cattle and small ruminants. Listeriosis is an infection by an intracelluar bacterium taking a similar course in cattle, goat and sheep and often results in lethal listeric encephalitis. Our group has shown that in vivo, in infected brains, iNOS is expressed in all species by a special subset of Mø within microabscesses, but cannot be detected in Mø of other sites, e.g. perivascular cuffs. These findings are discussed in the context of the wealth of paradoxical observations pointing to NO˙ either as a beneficial or a harmful mediator, depending on the exact site, the time, the virulence of an inducing pathogen, and the redox state of the cells in a given tissue.