Nitric oxide synthase (NOS) produces the critically important signaling molecule, nitric oxide (NO). Mammals have 3 NOS isoforms called endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). NO generated by eNOS maintains proper blood pressure and vascular flow, nNOS is involved with neuronal function, and iNOS produces NO as one means of combating infection in the immune system. The over production of NO by nNOS is a serious problem in neurodegenerative diseases given that NO is a reactive free radical and at high concentrations can lead to severe tissue damage. Since the discovery that NO is up regulated in several neural diseases, nNOS has been viewed as an important therapeutic target. However, the structure of all 3 isoforms are very similar and working out how to selectively target nNOS over eNOS has been challenging. Together with Rick Silverman (Northwestern) and using a combination of medicinal chemistry, computational methods, crystallography, and protein engineering compounds have been discovered that are 4,000 fold more selective for nNOS over eNOS and have nM affinity. This talk will tell the story behind this accomplishment together with current applications in neurodegenerative diseases, melanoma, and pathogenic bacteria.