Molecular testing for genetic and genomic variation has become an integral part of breast cancer management. Patients with a family history of breast cancer or other tumors, bilateral breast cancers, or early-onset breast cancers warrant genetic testing to determine whether a hereditary cancer syndrome is present. The availability of PARP inhibitors-drugs that are selectively active in BRCA1/2-associated breast cancers-has created the need for hereditary cancer testing for all patients diagnosed with advanced breast cancer. Tumor genomic profiling is the standard of care for many types of malignancies and is becoming increasingly important in the management of advanced breast cancer. Targetable mutations in advanced breast cancer include PIK3CA, HER2, and rare instances of mismatch deficiency or other targets for tyrosine kinase inhibitors. The development of methods for sequencing cell-free DNA should allow for broader and easier implementation of tumor genomic testing. Transcriptome-based expression signatures have become the standard of care in the management of early-stage estrogen receptor-positive breast cancers. These assays provide prognostic significance in the setting of adjuvant endocrine therapy and are predictive for benefit from adjuvant chemotherapy. Collectively, these developments underscore the contemporary reality that molecular testing is now part of the clinical management for the majority of patients with breast cancer.