This monograph focuses on the roles played by the subcellular NO-signaling microdomains in the prokaryote-, fungus-, plant- and animal cells and shows how NO behaves as an intracellular signal in distinct cellular environments. This monograph also provides a summary of our knowledge on how NO synthesis came through evolution to be associated with organelles and subcellular compartments. Promotes the novel ideas that some functions of NO and its associations with subcellular units have been conserved during the evolution of the cell. A special chapter is dedicated to the biomedical relevance of subcellular NO synthesis, and this chapter also discusses the evidence that altered compartmentalization of NO-producing enzymes causes disease.