NO is a key signaling molecule that has a wide range of biological functions including vasodilation and neurotransmission, and is implicated in several pathological conditions. Therefore, modulation of NO is a desired step in curbing the NO-associated disease processes. Targetting NOS proteins and inhibiting their activity to reduce NO production is a major approach since the inception of NOS inhibitor research. Although a series of NOS inhibitors have been developed, synthesized and practiced in experimental biology, no NOS inhibitor has been approved as yet a drug for therapeutic uses. The present review elaborates the scope of the clinical uses of NOS inhibitors and the inherent limitations of the process that makes the approach less successful so far in clinic.