A spectrum of adverse pregnancy outcomes, including preterm birth, low birth weight, and birth defects has been linked with maternal smoking during pregnancy. This article includes a review of studies investigating interactions between genetic variants and maternal smoking in contributing to birth defects using oral clefting as a model birth defect. The primary gene-smoking studies for other major birth defects are also summarized. Gene-environment interaction studies for birth defects are still at an early stage with several mixed results, but evolving research findings have begun to document clinically and developmentally important interactions. As samples and data become increasingly available, more effort is needed in designing innovative analytical methods to study gene-environment interactions.