Nitric oxide (NO) has emerged over the last 15 y as a mammalian metabolic intermediate that is involved in the regulation of critical physiological functions such as blood vessel homeostasis, neuronal transmission and host response to infection. NO is synthesized by the enzyme nitric oxide synthase, which converts the amino acid L-arginine to citrulline and NO. NO functions in biological systems in two very important ways. First, it has been found to be a messenger by which cells communicate with one another (signal transduction), and second, it plays a critical role in the host response to infection. In this second function, it appears that the toxic properties of NO have been harnessed by the immune system to kill or at least slow the growth of invading organisms. The nonspecific chemical reactivity with key cellular targets is responsible for this action. In signaling, NO directly activates the enzyme soluble guanylate cyclase (sGC). Once activated, sGC converts GTP to cGMP and pyrophosphate. The cGMP formed is responsible for the well-documented actions of NO such as blood vessel dilation. With the initial discovery of NO signaling, several important questions emerged that centered largely on the issue of how a signaling system functions when the signaling agent is chemically reactive (short lived), highly diffusible and toxic. Critical, especially in signaling, are the control of NO biosynthesis and interaction with the biological receptors at a concentration that will not harm the host. Why did Nature choose NO for the roles it has? That question engenders only speculation. How does NO work (i.e., what does NO do, and how does it do it without harm yet with specificity)? Answers to these questions can now be offered as the molecular level details emerge to form an interesting picture.