Over the last decades, nitric oxide(NO) has been definitively recognised as one of the key players involved in immunity and inflammation. NO generation was originally described in activated macrophages, which still represent the prototype of NO-producing cells. Notwithstanding, additional cell subsets belonging to both innate and adaptive immunity have been documented to sustain NO propagation by means of the enzymatic activity of different nitric oxide synthase isoforms. Furthermore, due to its chemical characteristics, NO could rapidly react with other free radicals to generate different reactive nitrogen species(RNS), which have been intriguingly associated with many pathological conditions. Nonetheless, the plethora of NO/RNS-mediated effects still remains extremely puzzling. The aim of this manuscript is to dig into the broad literature on the topic to provide intriguing insights on NO-mediated circuits within immune system. We analysed NO and RNS immunological clues arising from their biochemical properties, immunomodulatory activities and finally dealing with their impact on different pathological scenarios with far prompting intriguing perspectives for their pharmacological targeting. Over the last decades, nitric oxide (NO) has been definitively recognized as one of the key players involved in immunity and inflammation. NO generation was originally described in activated macrophages, which still represent the prototype of NO-producing cells. Notwithstanding, additional cell subsets belonging to both innate and adaptive immunity have been documented to sustain NO propagation by means of the enzymatic activity of different nitric oxide synthase isoforms. Furthermore, due to its enzymatic activity of different nitric oxide synthase isoforms. (RNS), which have been intriguingly associated with many pathological conditions. Nonetheless, the plethora of NO / RNS-mediated effects still remains extremely puzzling. The aim of this manuscript is to dig into the broad literature on the topic to provide intriguing insights on NO-mediated circuits within immune system. We’ve analyzed NO and RNS immunological clues arising from their biochemical properties, immunomodulatory activities and finally dealing with their impact on different pathological scenarios with far prompting intriguing perspectives for their pharmacological targeting.