In infants, smoke exposure is associated with more respiratory illnesses and decreased lung function. We hypothesized that perinatal lung is particularly susceptible to the damaging effects of cigarette smoke (CS) and that exposure to CS during this period may alter expression of immune response genes and adversely effect lung growth. To test this we exposed neonatal mice to fourteen days of CS. Immediately after exposure to CS, pulmonary gene expression profiling was performed on two week-old CS-exposed lung and age-matched control lung. Nitrotyrosine, TUNEL, MAC3 and phospho-SMAD-2 (p-SMAD2) staining was also performed. At eight weeks of age, lung volume measurements were determined and mean linear intercept (MLI) measurements were calculated. Pulmonary gene expression profiling revealed that CS exposure significantly inhibited type 1 and type 2 interferon pathway genes in neonatal lung, compared to age-matched control lung. Neonatal CS-exposed lung also had a significant increase in n-tyrosine, TUNEL and p-SMAD2 staining when compared to adult CS-exposed lung and age-matched control lung. Lung volumes at eight-weeks of age were modestly but significantly decreased in mice exposed to CS in the neonatal period compared to age-matched controls, consistent with impaired lung growth. The results of this study indicate that exposure to cigarette smoke during the neonatal period inhibits expression of genes involved in innate immunity and mildly impairs postnatal lung growth. These findings may in part explain the increased incidence of respiratory symptoms in infants and children exposed to cigarette smoke.