Cigarette smoking is the primary etiology of chronic obstructive pulmonary disease (COPD) and a risk factor for cardiovascular diseases. Smoking cessation results in a rapid decline of cardiovascular risk, but lung disease risk remains higher in former smokers compared to never smokers. Studying both pathologies in a single model is important, as they may have related causes and interactions. Therefore, we exposed ApoE-/- mice, which are prone to both premature atherosclerosis and emphysema, to either fresh air (sham), mainstream cigarette smoke (CS) for 6 months, or CS for 3 months followed by fresh air for 3 months (cessation group). Plasma, liver, and aorta samples were extracted for lipids and analyzed by mass spectrometry. While CS exposure increased most lipids, smoking cessation resulted in lower levels of many lipids in plasma and aortic arch. In parallel, gene expression profiles of lung parenchyma were obtained on microarrays. Findings obtained by lipidomics and transcriptomics were compared to standard toxicity assessments. For example, development of atherosclerosis in the aorta was assessed by plaque size in the aortic arch, while lung disease was evaluated by bronchoalveolar fluid (BALF) analysis and histological assessment of lung tissue. Gene set enrichment analysis of expression data from lungs of CS-exposed mice showed activation of pathways involved in cell proliferation and tissue remodeling that correlated with the general inflammation and emphysema observed in the lungs on histological evaluation. Interestingly, a progressive deactivation of these toxicity pathways was observed following CS exposure cessation. The potential of using animal models to study comorbidities associated with cigarette smoking and to investigate mechanistically potential benefits of smoking cessation was demonstrated. The study supports the applicability of this approach as a powerful tool to investigate disease mechanisms in vivo and to develop a systems biology-based risk assessment for modified risk tobacco products.