The inhibitory redox switches that we and others have identified impact several divergent protein kinase regions. For example, MEKK1 is targeted by oxidation of a cysteine residue within the ATP binding domain. PKA is oxidized within the activation loop in a manner that may regulate dephosphorylation of the activating threonine. PKG1 is activated through oxidation to form a cysteine-paired dimer. In other instances, several cysteine residues are oxidized, accompanying inactivation of the kinase, including JAK2,, and SAPK/JNK. In only a few instances have sites of oxidation been mapped to specific cysteines. On the other hand, kinases that are related to one another likely share functional regulatory mechanisms, including the inhibitory redox switch. We identified the surface cysteines C119 and C162 of p38 as major sites of oxidation using mutant studies. On the linear ICI 182780 subdomain map of p38 aligned with other protein kinases, C119 of p38 lies within subdomain V. Notably, p38 alpha and beta share a cysteine codon analogous to C119, while JNK1, 2, and 3 share a nearby cysteine in the same subdomain, and ERK isoforms lack cysteines in domain V. Cysteine C162, which is found in subdomain VIb, is shared among all p38 isoforms, and all JNK and ERK isoforms excepting ERK 3 and 4, but is otherwise lacking in other members of the CMGC kinase family. This observation leads to the prediction that these conserved cysteine residues may serve to control other MAP kinase family members much as they do p38. The ease by which specific cysteines and not others are oxidized may reflect the relative degree ionization of the target cysteine. Some oxidizable cysteines are also targets of electrophilic attack by drugs or signal-regulatory compounds originating outside the cell. For example the oxidized cysteine found in MEKK1 is also the target of covalent alkylation with phenylethylisothiocyanate and sulforaphane, cancer chemopreventive compounds containing an electrophilic isothiocyanate group. Other cysteines identified as oxidation sites thus represent potential sites of therapeutic regulation by drug candidates that may also covalently modify these target cysteines. Covalent targeting of regulatory cysteine residues is potentially the mechanism through which the protein kinase C inhibitor bisindolyl maleimide functions, since the maleimide moiety should make covalent bonds with target cysteines. While BIM is considered an ATP mimetic, we note that conventional and novel PKCs, that are inhibited by BIM, all have a cysteine residue within the ATP binding domain, while the atypical isoforms of PKC, which are resistant to BIM, lack this cysteine. This appears not to have been explored in the literature.