Breast cancer is one of the most frequently diagnosed cancers in women. It accounts for 23% of all cancers, with an estimated 1.15 million new cases in 2002. The role of the environment, such as reproductive factors, has been well studied in many epidemiological studies. Breast cancers also tend to cluster in families and are more common in monozygotic twins. Some of this clustering occurs as part of specific familial breast cancer syndromes where disease results from single alleles conferring a high risk. However, such alleles are rare in the population, and highly penetrant variants of BRCA1 and BRCA2 account for less than 20% of the genetic risk of breast cancer. The more common sporadic form of breast cancer are probably due to a polygenic inheritance of breast cancer susceptibility upon which environmental factors act upon resulting in breast cancer occurrence. Recent high-throughput genome-wide association studies are identifying several such genes, each with small absolute risk but with significant population level implications. The study of gene-environment interactions has thus far been confined to candidate gene approaches. The lack of large prospective cohorts with thousands of incident breast cancer cases makes the study of gene-environment interactions using a nested case-control design extremely difficult.