The role of stress in the pathogenesis of childhood wheeze remains controversial. Caretaker stress might influence wheeze through stress-induced behavioral changes in caregivers (e.g., smoking, breast-feeding) or biologic processes impacting infant development (e.g., immune response, susceptibility to lower respiratory infections). The influence of caregiver stress on wheeze in infancy was studied in a genetically predisposed prospective birth-cohort (n = 496). Caregiver-perceived stress and wheeze in the children were ascertained bimonthly from the first 2 to 3 mo of life. Greater levels of caregiver-perceived stress at 2 to 3 mo was associated with increased risk of subsequent repeated wheeze among the children during the first 14 mo of life (RR, 1.6; 95% CI, 1.3 to 1.9). Caregiver-perceived stress remained significant (RR, 1.4; 95% CI, 1.1 to 1.9) when controlling for factors potentially associated with both stress and wheeze (parental asthma, socioeconomic status, birth weight, and race/ethnicity) as well as mediators through which stress might influence wheeze (maternal smoking, breast-feeding, indoor allergen exposures, and lower respiratory infections). Furthermore, caregiver stress prospectively predicted wheeze in the infants, whereas wheeze in the children did not predict subsequent caregiver stress. The effect of caregiver stress on early childhood wheeze was independent of caregiver smoking and breast-feeding behaviors, as well as allergen exposure, birth weight, and lower respiratory infections. These findings suggest a more direct mechanism may be operating between stress and wheeze in early childhood. Stress may contribute significantly to the population burden of preventable childhood respiratory illness.