Sulfur mustard (SM) is a potent alkylating agent that induces cutaneous vesication. We are developing medical countermeasures to reduce the injury caused by SM exposure. Screening in the mouse ear vesicant model has identified three lead compounds: British anti-lewisite (BAL), indomethacin, and octyl homovanillamide. To understand the molecular mechanism of action of these compounds we used oligonucleotide microarrays to compare gene expression profiles in unexposed skin (vehicle control), SM-exposed skin, and skin pretreated with each compound before SM exposure. Male CD-1 mice were topically exposed on the inner surface of the right ear to SM alone or pretreated for 15 minutes with one of the lead compounds and then exposed to SM. Left ears were vehicle-exposed. Skin tissues were harvested 24 hours later for ear weight determination (an endpoint indicating compound efficacy). RNA was extracted from the tissues and used as starting material to probe oligonucleotide microarrays. The gene expression data were analyzed using principal component analysis (PCA) to identify sources of data variability. Our PCA results reveal partitioning of the samples based on drug treatment and SM exposure. Vehicle-exposed mouse ears cluster together away from the other treatment groups. Mouse ears pretreated with BAL or octyl homovanillamide cluster more closely with vehicle-exposed ears, while indomethacin-treated mouse ears cluster more closely with SMexposed ears. This clustering of the samples is supported by the relative ear weights, in which the indomethacin group has ear weights closer to the SM-exposed group, whereas the BAL and octyl homovanillamide groups have ear weights closer to the vehicle-exposed group. These data provide the basis for understanding what gene expression changes are important in the development of efficacious SM exposure treatments.