Breast cancer is the leading lethal malignancy of women all over the world. Epidemiological studies have shown that higher age and a positive family history of breast cancer are associated with the highest risk. Familial clustering of breast cancer, often in conjunction with cancer at other sites, is frequently caused by a hereditary disposition. Mutations in known breast cancer susceptibility genes include BRCA1 and BRCA2 mutations conferring a high life-time risk for breast cancer up to 85%, or CHEK2, ATM and NBS1 mutations with a lower penetrance. The products of these genes are involved in DNA double-strand break signaling and repair, and considerable progress has been made during the past years to identify the mutational spectra of these genes in familial and sporadic breast cancer. The recognition of monogenic breast cancer predisposition syndromes is critical as there is also a risk of other cancers in addition to an elevated risk of contralateral breast cancer. However, the known genes explain only a minor proportion of breast cancer cases whereas epidemiological studies indicate that most breast cancer is, at least in part, due to an inherited susceptibility. Hereditary and environmental factors may have acted synergistically in many cases to modulate the probability and progression of the disease. For instance, ionizing radiation is for long time being recognized as a potent carcinogen that leads to DNA double strand breaks (DSBs) – the most severe type of DNA damage – and increases breast cancer risk in exposed young women. Variations in the genes involved in the cellular responses towards ionizing radiation are thus under special consideration as possible breast cancer susceptibility alleles. Large association studies are presently being conducted worldwide and have already uncovered some more common genetic variants that modulate breast cancer risk. While each of these low-penetrance alleles confers only a small increase or decrease in risk, their combination might be clinically relevant. Cancer genetics is becoming increasingly integrated into oncological care, particularly in breast cancer management.