Rat postimplantation whole-embryo culture (WEC) is a promising alternative test for the assessment of developmental toxicity. Toxicogenomic-based approaches may improve the predictive ability of the WEC model by providing a means to identify compound-specific mechanistic responses associated with embryotoxicity in vivo. Furthermore, alterations in gene expression may serve as a sensitive, objective, and robust marker, which precedes the observation of classical developmental toxicity endpoints in time. In this study, in combination with morphological developmental assessments, we studied transcriptomic responses associated with four distinct teratogens (caffeine [CAF], methylmercury [MM], monobutyl phthalate, and methoxyacetic acid) after 4 h of exposure, well before apparent embryotoxicity in WEC. We evaluated gene expression changes associated with similar levels of induced morphological embryotoxicity for each teratogen (as determined by total morphological score), evaluating for functional enrichment and quantitative changes in response. Concentrations selected for each of the four teratogens used induced a number of common effects on embryonic development (neural tube closure and optic/otic system). Despite inducing common morphological effects, our analysis suggests limited overlap in terms of toxicogenomic response at the gene expression level and at the level of biological processes across all four test chemicals. Many unique responses associated with each chemical correlated with previously hypothesized modes of developmental toxicity. For example, alterations in developmental signaling and cholesterol metabolism were observed with MM and CAF, respectively. This initial study suggests that distinct chemically induced toxicogenomic responses precede morphological effects in WEC and that these responses are relevant with mechanisms of toxicity previously observed in vivo.