Background Prenatal origins of wheezing are not fully understood. This study develops a model of mechanisms linking perinatal stress exposure to wheeze phenotypes in children. Methods Data were obtained from 1,849 mother-child dyads participating in ELSPAC-CZ birth cohort. Wheeze phenotypes assessed between birth and age seven years included “never wheeze”, “early-onset transient (EOT) wheeze,” “early-onset persistent (EOP) wheeze,” and “late-onset (LO) wheeze.” Prenatal and postnatal maternal stress exposures were assessed in mid-pregnancy and six months post-delivery, respectively, using an inventory of 42 life events. Results In adjusted models, children in the highest tercile (high) vs. lowest tercile (low) of prenatal life events had a 44% higher risk of EOT wheeze (relative risk ratio [RRR]=1.44, 95% confidence interval [CI]=1.06-1.95, p=0.02) and 69% higher risk of LO wheeze (RRR=1.69, 95% CI=1.13-2.52, p=0.01). High vs. low exposure to postnatal life events predicted a 74% increase in the risk of EOT wheeze (RRR=1.74, 95% CI=1.27-2.38, p<0.001) and 101% increase for EOP wheeze (RRR=2.01, 95% CI=1.23-3.26, p=0.005). Postnatal life events partially mediated between prenatal life events and any wheeze (high vs. low life events: indirect effect OR=1.13, 95% CI=1.06-1.21, p<0.001). Lower respiratory tract infections and secondary smoke partially mediated between postnatal life events and any wheeze (indirect effects OR=1.06, 95% CI=1.02-1.09, p=0.002 and OR=1.02, 95% CI 1.001-1.05, p=0.035, respectively). Conclusions Exposures to prenatal and postnatal life events are risk factors for development of wheezing. Prenatal stress contributes to wheeze directly and also through postnatal life events and respiratory infections.