Certain types of low molecular weight chemicals have the ability to cause respiratory sensitization via haptenation of carrier proteins. It has been suggested that such chemicals must contain multiple "reactive" functional groups to elicit an immune response. In contrast to the well-developed electrophilic reaction chemistry ideas detailing the initial haptenation event for skin sensitization, no detailed mechanistic chemistry analysis has been performed for respiratory sensitization. The aim of this study, therefore, was to perform an electrophilic reaction chemistry analysis to explain the differing respiratory sensitizing potentials of 16 chemicals containing both single and multiple functional groups. The analysis has been supported by quantum chemical calculations probing the electrophilicities of the reactive chemicals. These calculations suggest that within each mechanistic category differing "reactivity thresholds" exist that must be passed for respiratory sensitization to occur. In addition, this study highlights how such mechanistically driven category formation could be used as an in silico hazard identification tool.