Despite years of research, the etiology of most birth defects remains largely unknown. Interview instruments have been the major tools in the search for environmental causes of birth defects. Because of respondents’ problems with recognition and recall, interviews are limited in their capacity to measure certain exposures. Laboratory scientists can have a major impact on defining markers of environmental exposure and genetic susceptibility. The Centers for Disease Control is starting a case‐control study of serious birth defects on the basis of a population‐based surveillance system for birth defects diagnosed during the first year of life in metropolitan Atlanta. Each year, 300 infants with selected birth defects (case subjects) and 100 population‐based control subjects (infants without birth defects) will be enrolled in an ongoing study that will supplement surveillance. In addition to conducting extensive maternal interviews, we will collect blood and urine specimens from case and control subjects and their mothers for laboratory testing. Eventually, some environmental sampling may be incorporated. Particular areas of emphasis are (1) nutritional factors, specifically measuring maternal folic acid levels and other micronutrients (e.g., zinc) to explore their role in the etiology of neural tube defects, (2) substance use, specifically measuring cocaine metabolites in the blood and urine to explore their role for specific vascular disruption defects, and (3) environmental factors such as pesticides and aflatoxins, to explore their potential relationships with specific defects. In addition, a DNA bank will be maintained to evaluate the role of specific candidate genes in the etiology of birth defects. The development and testing of these methods could be useful to assess the interaction between environmental exposures and genetic susceptibility in the etiology of birth defects.