Irritant contact dermatitis (ICD), the most common occupational cutaneous illness, is an acute inflammatory response caused by topical irritant exposure. Multiple factors are associated with the manifestation and severity of ICD and contribute to the lack of effective prophylactic and treatment strategies. To determine the pathomechanism of ICD caused by the irritants, benzalkonium chloride (BKC) and JP-8 jet fuel, 2 mouse strains, C57BL/6 and Balb/c, were assessed due to their differential immune predispositions. Dermatitis lesions were obtained for histological examination, cytokine protein expression analysis, and determination of immune cell infiltration via flow cytometric analysis. Following acute (3-day) BKC exposure C57BL/6 skin displayed increased neutrophils and expression of 19 distinct cytokines, but fewer dendritic cells and lower expression of IL-1α and IL-9 as compared with Balb/c skin. Following prolonged (7-day) exposure to BKC, inflammatory cell populations trended similar to 3-day exposure; however, only 6 distinct cytokines were higher in C57BL/6, whereas Balb/c displayed higher expression of IL-27, 28, and 31. Following acute JP-8 exposure, C57BL/6 skin displayed higher levels of γδ T cell infiltration, G and M-CSF expression, but lower populations of neutrophils, monocytes, and dendritic cells compared with Balb/c skin. As with BKC, skin inflammatory cell populations following 7-day JP-8 exposure trended similar to 3-day exposure. However, C57BL/6 skin displayed higher levels of IL-6 and LIF, whereas Balb/c showed increased IL-1β, IL-27, G-CSF, TNFα, and 7 additional chemokines. These findings further define the pathology of ICD, partially explain individual variation of ICD, and offer insight into biomarkers for risk assessment.