A variety of mouse models has been used in understanding the pathogenesis of pulmonary emphysema/COPD. It is thought that the effect of cigarette smoke (CS) is strain-dependant because certain mouse strains are more susceptible or resistant to develop emphysema. However, the molecular basis of susceptibility of mouse strains to CS is not known. We studied the effect of CS on lungs of most commonly used mouse strains so as to understand the molecular mechanism of susceptibility to CS. C57BL/6J, A/J, AKR/J, CD-1 and 129SvJ mice were exposed to CS for three consecutive days, and various parameters of inflammatory and oxidative responses were assessed in lungs of these mice. We found that the C57BL/6J strain was highly susceptible, whereas the A/J, AKR/J and CD-1 strains were moderately susceptible, and the 129SvJ strain was resistant to lung inflammatory and oxidant responses in response to CS exposure. The mouse strain which was more susceptible to CS showed augmented lung inflammatory cell influx, activation of NF-B and p38 MAPK, increased levels of MMP-9 and NF-B-dependent pro-inflammatory cytokines compared to resistant mouse strains. Similarly, decreased levels of glutathione were associated with increased levels of lipid peroxidation products in susceptible mouse strains compared to resistant strains. Hence, we identified the susceptible and resistant mouse strains based on the pattern of inflammatory and oxidant responses. Identification of sensitive and resistant mouse strains could be useful for studying the molecular mechanisms of effects of CS on inflammation, and pharmacological interventional studies in CS exposure mouse models.