ABSTRACT Birth defects are the leading cause of infant mortality in the US. Birth defects also have enormous associated emotional and fiscal costs. The California Center’s research efforts, both independently and in collaboration with other Centers for Birth Defects Research and Prevention contributing to the National Birth Defects Prevention Study (NBDPS) and the Birth Defects Study to Evaluate Pregnancy Exposures I (BD-STEPS I) have been at the forefront of public health birth defects research. With this new funding opportunity (BD- STEPS II), our Center will further enhance scientific understanding of the potential causes of specific birth defects, which will undoubtedly have important implications for risk assessment and prevention of common, costly, and deadly birth defects. In this application we propose the following aims: Aim 1: Enhance the epidemiologic public health research capacity of the Centers for Birth Defects and Research and Prevention by actively participating in BD-STEPS II in a region of the US that is highly diverse in its race/ethnicity as well its environmental exposures. Aim 2: Utilize data from BD-STEPS I and II as well as NBDPS (and likely other data sources unique to California) to conduct rigorous collaborative and local studies that will identify potential modifiable risk factors for selected birth defects (and where appropriate, in combination with genetic susceptibility) to reduce the public health burden of birth defects in the US. The California Center is well-equipped to contribute to BD-STEPS II – it is a world leader in birth defects epidemiology and highly experienced in the development, data collection and dissemination of information from population-based studies of birth defects, exemplified by its outstanding performance within the CDC Centers for Birth Defects Research and its highly innovative research portfolio. The application describes how the California Center will accomplish Aims 1 and 2 and will thereby further the knowledge base about causes and prevention for human birth defects. The California Center has extensive experience conducting research related to the BD-STEPS II areas of focus, which include maternal chronic diseases and their treatment, infectious disease in pregnancy, and medications. We have proposed several analytic inquiries, complemented by the use of additional innovative datasets and analytic approaches, which will enable us to collaboratively continue elucidating the contribution of these and other modifiable risk factors to birth defects.