Abstract: Risk factors of birth defects are various and complex. So far, up to 50% of birth defects can not be attributed to a single cause. According to the present study, risk factors of birth defects can be divided into four categories: (1) monogenic inheritance, such as hemophilia, achondroplasia, and cystic fibrosis; (2) numerical abnormality of chromosome, such as Downs syndrome; (3) teratogenic environmental factors, such as Phocomelia and alcohol syndrome; (4) gene-environment interactions, including cleft lip and palate, congenital heart disease, and neural tube defects. Therefore, multiple variables shall be taken into account and confounding factors should be ruled out for the birth defects risk factors study to obtain a reliable finding.