The major genetic risk factor for MBC is inherited mutation of the BRCA2 gene such that carriers have a cumulative incidence of 6.9% up to age 80. Among 51 families with BRCA2 mutations, only 5 BRCA1 and 5 CHEK2, were found despite a predicted high likelihood. In worldwide cohorts, the median number of BRCA1 cases was 0.6 compared with 10 BRCA2 carriers. Truncated PALB2 mutations were found in 10/923 men with familial breast cancer but in none of the 1084 controls. In 48 sporadic Italian MBC cases PALB2 mutation was found in one case suggesting a small but important role in MBC. EMSY amplification was present in 35% of specimens from 75 MBC cases and levels were low in BRCA2-associated cancers. Other minor genetic players in MBC include ATM, CHEK2, AR, PIK3CA, and CYP17. After genetic testing, of 83 female carriers who had developed breast cancer, 71% chose risk reducing surgery whereas all 41 male carriers chose surveillance only. Uptake of testing may be improved by Web-based genetic education.