The existence of hazardous substances in the workplace has raised concerns about the potential of these substances for adverse reproductive effects. Identification of associations between parental occupational exposures and congenital malformations in the offspring may provide the opportunity for preventing such exposures and thus reduce the risk of malformations. However, there are many methodological considerations inherent in studying the potential relation between parental occupational exposures and congenital malformations in the offspring. Considerations relating to outcome include methods and timing of ascertaining cases with malformations, diagnostic criteria, and problems in grouping malformations for purposes of analysis. With regard to measuring exposures, issues include methods for obtaining valid estimates of the nature, duration, timing of exposure, and exposure-response relationship. Other methodological issues discussed include selection of appropriate reference groups, sample size, and multiple hypothesis testing.