In the body, nitric oxide (NO) is an important physiological regulator of functions such as vasodilatation and neurotransmission. Under pathological conditions, high concentrations of NO can be either beneficial(e.g. anti-bacterial, anti-parasitic and anti-viral) or detrimental; NO can therefore be considered a double-edged sword. When manipulating NO levels clinically, attention should be paid to minimize the negative effects and maximize the beneficial effects of NO. This article highlights recent evidence that supports the complexity of the regulatory mechanisms that lead to sophisticated endogenous NO production.