The diatomic gas nitric oxide (NO) serves dual physiological roles as both a signaling molecule and an inflammation agent. Nitric oxide synthases (NOS) are large, multi-domain hemoproteins responsible for production of NO. Emitted at minute concentrations, NO is a membrane-permeable paracrine signaling agent. Generated at high levels, NO acts as a potent cytotoxic weapon of the immune system. As a fairly reactive free radical, NO production is tightly regulated. NOS regulation is especially important for synaptic NO signaling. NO is uniquely well-suited for local, omnidirectional neurotransmission because it is a short-lived, freely diffusible gas. Unlike classical neurotransmitters, NO cannot be stored in vesicles. Control over NO signaling is exerted by regulating localization and activation. Strict regulation of NO production is vital, as NO surges are a prominent mediator of excitotoxicity.