Congenital heart disease (CHD) is an enigma. It is the most common human birth defect, and yet, even 31 with the application of modern genetic and genomic technologies, only a minority of cases can be 32 explained genetically. This is because environmental stressors also cause CHD. Here we propose a 33 plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that 34 exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart 35 defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly 36 reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus UPR activation during 37 human pregnancy may be a common cause of CHD. Our findings have far-reaching consequences 38 because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, 39 our discovery could lead to preventative strategies to reduce the incidence of human CHD.