Sulfur mustard (bis-(2-chloroethyl) sulfide) is an alkylating agent, and produces blisters on skin and causes systemic toxicity and DNA strand breaks. The mechanism and role of inflammatory cytokines, receptors, and DNA damage signaling pathway specific genes were studied in sulfur mustard (SM) exposed mouse liver. Female mice were exposed percutaneously with 1.0L.D50 of SM (8.1mg/kg body weight). Inflammatory cytokine gene expression profiles were determined at 1 and 3 days post-exposure to SM and DNA damage signaling pathway specific, double strand break repair proteins gene expression profile at 1, 3, and 7 days were examined by DNA microarrays and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Anti-inflammatory cytokines and receptors were down-regulated from day 1 to day 3. Pro-inflammatory genes TNF-α, TNF receptors were up-regulated from day 1 to day 3. Double strand DNA break repair proteins Rad23, Rad50, Rad51, Rad52, and Rad54l were down-regulated from day 1 to day 7. This result indicates sulfur mustard causes inflammatory response, activates the cascade of events in the signal transduction pathway, and promotes irreversible double strand DNA breaks in chromosomal DNA, which is leading to cell death.