The participation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) in intracellular signaling is widely documented. Nonetheless, it has been difficult to understand how their involvement meets the requirement of signaling for specificity, and hence, to accept that their role could be physiologic. The problem can be resolved by adducing three postulates:(a) to execute and coordinate multiple adaptations to a changing environment, intracellular signaling requires several different types of specificity;(b) based on the chemistry of the mediators, types of specificity can be distinguished by whether an intermediate in a signaling pathway regulates additional pathways that are physically noncontiguous with the one in which it was formed, and if it does so, whether it acts like an on/off switch or a rheostat; and (c) a given mediator can have specificity of more than one type.

Type I specificity involves intermediary interactions that are initiated noncovalently based on complementarity of molecular shape. Members of a type I signaling pathway are colocalized such that information is private to a given pathway and flows in a linear manner. Type II specificity also involves initial interactions that are based on complementarity, but the mediators diffuse to switch on or off some pathways that are not colocalized with the pathway that generates them. Type III specificity involves covalent interactions as the initial interaction of one signaling intermediate with another. Mediators exerting type III specificity diffuse to affect multiple targets that are not colocalized, where their major function is to regulate how these pathways respond to their own individual agonists. Mediators acting with specificity of types II and III convey information publicly, that is, across much of the cell. ROI and RNI can serve as agonists to activate pathways that operate with type I or type II specificity, but for the most part, endogenous ROI and RNI behave with specificity of the third kind.