Ethanol is a well-known teratogen. While this teratogenic potential is well-characterized clinically, the mechanisms through which ethanol exposure results in developmental defects remain unclear. Here we use the zebrafish model to elucidate eye-specific mechanisms that may underlie ethanol-mediated microphthalmia (reduced eye size), using time-series microarray analysis of gene expression of eye tissues of embryos exposed to 1.5% ethanol vs. untreated embryos. We identified 62 genes differentially expressed in ethanol-treated as compared to control zebrafish eyes from all sampling times over the period of retinal neurogenesis (24-48 hours post-fertilization). Application of the EDGE (extraction of differential gene expression) algorithm identified over 3000 genes differentially expressed over developmental time in ethanol-treated embryo eyes as compared to untreated embryo eyes. These lists included several genes indicating a mis-regulated cellular stress response (heat shock response) due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino (MO) targeting heat shock factor 1 (hsf-1) mRNA resulted in a microphthalmic phenotype, suggesting convergent molecular pathways. Manipulation of the heat shock response by thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. Together these data are consistent with roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure in zebrafish.