Abstract: Nitric oxide (NO) has long been known to be an intermediate in bacterial pathways of denitrification. It is only since the middle to late 1980s that it was found to play a central role in a much broader biology context. For example, it is now well established that NO acts as a signaling agent in higher organisms. Yet NO is toxic and reactive under biological conditions. How is the biology carried out by NO controlled? How is NO used and the inherent toxicity avoided? How do organisms tell the difference between NO and O2? What is the biological output? A molecular perspective on ligand discrimination in hemoproteins has emerged as has a further understanding and predictions about selective ligand sensing and function in biology.