The combined observation that 20-30% of all patients with breast cancer have a family history of the disease and the results from twin studies showing that 25% of breast cancer cases are heritable, indicate that this malignancy is one of the most commonly inherited cancers. Discovery of the BRCA1 and BRCA2 genes more than a decade ago has had a tremendous impact on patient care allowing for early detection and prevention of breast cancer. However, deleterious mutations within the BRCA1 and BRCA2 genes cause at most 3-8% of all breast cancer cases. New data indicate that genomic rearrangements within the same genes may occasionally identify additional carriers of nonfunctional BRCA1 and BRCA2 genes. Such genomic rearrangements are missed by conventional sequencing. The remainder of the unexplained familial risk is presumably due to other yet unidentified high penetrance genes, but polygenic mechanisms and high frequency low penetrance tumor susceptibility genes are likely to account for a greater proportion of familial breast cancers. In this regard, there is growing evidence that a common variant of the type I TGF-ss receptor, TGFBR1*6A, may account for approximately 5% of all breast cancer cases, a fraction similar to that attributable to BRCA1 and BRCA2. Such genes may also modify the penetrance of the BRCA1 and BRCA2 genes. In the next decade, screening for combinations of high and low penetrance genes will likely permit the identification of a large fraction of inherited breast cancer cases and will further reduce the burden of familial breast cancer.