Most human birth defects are thought to result from complex interactions between combinations of genetic and environmental factors. This is true even for conditions that, at face value, may appear simple and straightforward, like fetal alcohol spectrum disorders (FASD). FASD describe the full range of structural and neurological disruptions that result from prenatal alcohol exposure. While FASD require alcohol exposure, evidence from human and animal model studies demonstrate that additional genetic and/or environmental factors can influence the embryo's susceptibility to alcohol. Only a limited number of alcohol interactions in birth defects have been identified, with many sensitizing genetic and environmental factors likely yet to be identified. Because of this, while unsatisfying, there is no definitively "safe" dose of alcohol for all pregnancies. Determining these other factors, as well as mechanistically characterizing known interactions, is critical for better understanding and preventing FASD and requires combined scrutiny of human and model organism studies.