Congenital cardiovascular malformations are the most common form of birth defect recorded. Specific malformations of the outflow portions of the heart are termed conotruncal malformations and arise from the septation of the common conotruncus of the heart. There are multiple lines of evidence that point towards genetic–environmental interactions in the genesis of conotruncal congenital cardiovascular malformations. In particular, environmental exposures that involve vitamin A, retinol, folic acid or retinol receptors are identified as cardiac teratogens. Other environmental agents for which there is evidence of cardiac teratogenicity for outflow tract malformations include nitrofen, ambient air pollution, chlorinated hydrocarbons and pesticides. Genetic polymorphisms of xenobiotic metabolism are clearly differentiating in the effect of potential teratogens. Work in this field is at a new cusp, with the ability to measure xenobiotic exposure, document xenobiotic metabolizing genetic polymorphisms and integrate these data into models of cardiac teratogenesis.