Congenital heart disease (CHD) is the most common form of birth defect in humans and, despite extensive research, genetic causes have only been identified in a minority of cases. At least 100 genes have been implicated with varying degrees of penetrance, suggesting that many cases of CHD result from gene-gene or gene-environment interactions. However, the relationship between genetic susceptibility and environmental factors is poorly understood. Now, Sally Dunwoodie and colleagues investigate the effects of gestational hypoxia in genetically susceptible mice. They discover that mutations in CHD-associated genes, such as Nkx2-5, increase the incidence of heart defects and embryo lethality following short-term hypoxia. For Nkx2-5 heterozygous-null embryos, hypoxia causes variable embryonic heart morphology, reduced heart rate and sudden death. Although in normal oxygen conditions (normoxia), expression of Nkx2-5 is comparable between wild-type and Nkx2-5+/− embryos, hypoxia reduces levels of Nkx2-5 mRNA and protein in the heterozygotes. The authors correlate phenotype penetrance in Nkx2-5+/− embryos with levels of nuclear hypoxia inducible factor 1α (HIF1α). They show that in normoxia, chemical stabilisation of nuclear HIF1α can reduce Nkx2-5 mRNA and protein levels and increase heart defects, implying that sustained expression of HIF1α is important. Although the mechanisms underlying these interactions are not fully understood, this study provides new links between environmental conditions and cardiac defects and embryo lethality in genetically susceptible mice.