This article reviews the mechanisms of nitric oxide (NO)-related antimicrobial activity and its role in host-pathogen interactions. NO, a small and potent molecule, is produced by mammalian cells through the enzymatic oxidation of l-arginine and plays a dual role in infection: it can contribute to morbidity by acting as a vasodilator, myocardial depressant, and cytotoxic mediator, but it also has microvascular, cytoprotective, immunoregulatory, and antimicrobial properties. The antimicrobial activity of NO is supported by various lines of evidence, including increased NO production in response to proinflammatory cytokines and microbial products, correlation between NO production and microbial control in animal models, and in vitro studies demonstrating NO-dependent microbistatic or microbicidal activity. NO has been particularly implicated in host defenses against intracellular pathogens and in maintaining microbial latency. The article also discusses the interactions between NO and reactive oxygen intermediates, which can form antimicrobial molecular species such as peroxynitrite, S-nitrosothiols, and nitrogen dioxide. These interactions can enhance the antimicrobial function of the respiratory burst while protecting tissues from oxidant injury. Additionally, the article explores how NO enters microbial cells and its targets within microbial cells, including DNA, proteins, and lipids. Finally, it reviews microbial defenses against NO, which include antioxidant defenses, specific stress regulons, scavengers, detoxifying enzymes, repair systems, and strategies to avoid phagocytosis or stimulate NO synthase. The accumulating evidence suggests that NO-related species derived from NO synthase have significant antimicrobial activity and play crucial roles in host defense against various pathogens.This article reviews the mechanisms of nitric oxide (NO)-related antimicrobial activity and its role in host-pathogen interactions. NO, a small and potent molecule, is produced by mammalian cells through the enzymatic oxidation of l-arginine and plays a dual role in infection: it can contribute to morbidity by acting as a vasodilator, myocardial depressant, and cytotoxic mediator, but it also has microvascular, cytoprotective, immunoregulatory, and antimicrobial properties. The antimicrobial activity of NO is supported by various lines of evidence, including increased NO production in response to proinflammatory cytokines and microbial products, correlation between NO production and microbial control in animal models, and in vitro studies demonstrating NO-dependent microbistatic or microbicidal activity. NO has been particularly implicated in host defenses against intracellular pathogens and in maintaining microbial latency. The article also discusses the interactions between NO and reactive oxygen intermediates, which can form antimicrobial molecular species such as peroxynitrite, S-nitrosothiols, and nitrogen dioxide. These interactions can enhance the antimicrobial function of the respiratory burst while protecting tissues from oxidant injury. Additionally, the article explores how NO enters microbial cells and its targets within microbial cells, including DNA, proteins, and lipids. Finally, it reviews microbial defenses against NO, which include antioxidant defenses, specific stress regulons, scavengers, detoxifying enzymes, repair systems, and strategies to avoid phagocytosis or stimulate NO synthase. The accumulating evidence suggests that NO-related species derived from NO synthase have significant antimicrobial activity and play crucial roles in host defense against various pathogens.