The objective of this study was to characterize the impact of cigarette smoke exposure on lung immune and inflammatory processes. BALB/c and C57BL/6 mice were exposed to cigarette smoke for 4 days (acute) or 5 weeks (prolonged). Both mouse strains manifested an inflammatory response after acute smoke exposure, characterized by an influx of neutrophils, and mononuclear cells. Multiplex analysis revealed a greater than two fold increase of the cytokines IL-1, IL-5, IL-6, and IL-18, as well as the chemokines MCP-1 and 3, MIP-1, , and , MIP-2, MIP-3, MDC, GCP-2, and IP-10. In BALB/c mice, neutrophilia persisted following prolonged exposure, while C57BL/6 showed evidence of attenuated neutrophilia both in the BAL and the lungs. In both mouse strains, cigarette smoke exposure was associated with an expansion of mature (CD11c^hi/MHC class II^hi) myeloid dendritic cells; we observed no changes in plasmacytoid dendritic cells. Lymphocytes in the lungs displayed an activated phenotype that persisted for CD4 T cells only after prolonged exposure. In BALB/c mice, T cells acquired Th1 and Th2 effector function after 5 weeks of smoke exposure, while, in C57BL/6 mice, neither Th1 nor Th2 cells were detected. In both mouse strains, cigarette smoke exposure led to an accumulation of FoxP3⁺ T regulatory cells in the lungs. Studies in RAG1 knock out mice provided evidence that these regulatory cells participate in controlling smoke-induced inflammation. Acute and chronic cigarette smoke exposure was associated with inflammation, activation of the adaptive immune system, and expansion of T regulatory cells in the lungs.