Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. Until the genome-wide association study on page 1087 was published online, known susceptibility genes — such as BRCA1 and BRCA2 — accounted for less than 25% of the familial risk of breast cancer. The new study, which involved 21,860 patients and 22,578 controls, has identified four genes positively associated with genetic susceptibility to breast cancer (FGFR2, TNRC9, MAP3K1 and LSP1). Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the newly discovered associations appear to relate more to the control of cell growth or to cell signalling. Only one of the genes — FGFR2 — had a clear prior relevance to breast cancer. The identification of these genes opens up new avenues of research into the causes of breast cancer. They may also become part of a new strategy to classify women's risk, paving the way for better disease prevention. Previous work has identified several genes where mutations lead to breast cancer, but other genetic and environmental factors must still be accounted for. A large study of genetic association with breast cancer points to four novel genes and many more genetic markers that should be pursued for their link to cancer susceptibility.