Oncotype DX, PAM50, and MammaPrint are multigene tests that are being used clinically for early-stage breast cancer to predict recurrence risk and guide adjuvant chemotherapy decisions. These tests have been validated in multiple retrospective studies, and prospective clinical trials are in progress. The TAILORx trial uses the Oncotype DX recurrence score to assign estrogen receptor–positive (ER+), node-negative patients to chemotherapy plus hormonal therapy versus hormonal therapy alone. The RxPONDER (SWOG S1007) trial uses Oncotype DX in a similar approach but on node-positive patients, and it includes the PAM50 test as a secondary analysis. The MINDACT trial uses Mamma-Print and Adjuvant! Online for treatment arm assignments. MINDACT has very broad eligibility criteria and 2 secondary randomizations for selecting chemotherapy and hormonal therapy regimens. This article discusses how the latest results on cancer genome sequencing apply to early-stage breast cancer. Several hundred breast cancers have already undergone genome sequencing, and the somatic DNA changes found in the tumor, compared with the patient's normal DNA, have been identified. Higher rates of point mutations and chromosomal translocations are found in aromatase inhibitor–resistant ER+ cancers and in the basal-like and HER2-enriched breast cancer subtypes. Correlations of somatic mutations with neoadjuvant aromatase inhibitor response are discussed. Genome sequencing can potentially identify the molecular abnormalities that underlie the poor risk identified by multigene tests and provide potential new targets for therapy, but more clinical trials correlating clinical outcome and somatic DNA changes are needed.