The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.