This article presents an overview of electrophilic reaction mechanisms relevant to skin sensitization, with reference to a published skin sensitization test data set for 106 chemicals. Where appropriate to aid the interpretation, additional data on a small number of further compounds are also discussed. It is shown that there is a close correspondence in the way differences and similarities in skin sensitization potency of chemicals relate to differences and similarities in their physical organic chemistry and electrophilic reaction mechanistic chemistry. The 106 chemicals are classified into their reaction mechanistic applicability domains, and reactivity-sensitization trends are analyzed for each domain: the Michael acceptor and pro-Michael acceptor electrophile domain; the SNAr electrophile domain; the SN2 electrophile domain; the Schiff base electrophile domain; the acyl transfer electrophile domain; and the non-electrophilic non-pro-electrophilic domain. The last of these domains should be populated mainly by non-sensitizers. Classification of 87 of the 106 compounds, using these domains, was straightforward. In most of the domains and subdomains where there are sufficient compounds, clear trends can be seen, in conformity with the Relative Alkylation Index (RAI) model, between sensitization potential and reactivity/hydrophobicity. Of the remaining 19 compounds, 7 are alpha-X-methyl-gamma-lactones that on the basis of published organic chemistry studies and guinea pig sensitization data can be classed as pro-Michael acceptors by elimination of HX but that are mostly negative in the LLNA, indicating a difference in bioactivation capabilities between mice and guinea pigs. The other 12 compounds, whose chemistry was not immediately obvious, were found after further analysis and literature research to fit into appropriate mechanistic domains that rationalize their skin sensitizing properties.