Signaling by redox state regulates the transcriptional and post-transcriptional events that control gene expression. To elucidate redox signaling in vivo, the effects of the reductive intracellular redox environment on regulatory redox events must be taken into account. This article focuses on proteins that contain regulatory disulfides, considering whether regulatory proteins can be oxidized and how the redox state of regulatory proteins can be uniquely controlled to allow redox signaling via specific pathways. It is possible that the favored kinetics of the redox reactions of regulatory proteins are important for attaining specificity in redox signaling.