Part 1: Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. Whole-exome and shallow whole-genome sequencing were employed to identify genes and pathways preferentially mutated or copy-number altered in breast cancer metastases compared with the paired primary tumors in patients. Seven genes were preferentially mutated in metastases: MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Part 2: It remains unclear whether alterations that drive breast cancer metastasis arise after dissemination or were originally present and selected for within rare subclones in the primary tumor. To this end, ~200 regions of interest were sequenced in both paired primary and metastatic tumors using ultra-deep sequencing coupled with unique molecular identifiers (UDS-UMI) and mitigation of FFPE-artifacts by uracil deglycosylase. Rare subclonal mutation burden within primary tumors was associated with advanced stage at diagnosis and an increased frequency of alterations known to be associated with primary tumorigenesis, and predicted the acquisition of specific metastasis-enriched genomic alterations in metastases, including: gain of ERBB2 and PTK6; mutations in the focal adhesion, mTOR, WNT, and cAMP signaling pathways; and nuclear localization of activated PKA. The majority (85%) of metastasis-specific mutations remained undetected in primary tumors, indicating that they were either present in less than ~2-5% of cells within the primary tumor, occurred within unassayed regions, or arose after metastatic dissemination. In a quarter of patients, metastasis-specific mutations were detected within rare subclones in primary tumors, including a 2% cellular subclone that bore mutations in both the WNT receptor, LRP5, and the metastasis-enriched gene, PEAK1. UDS-UMI enabled the detection of poly-clonal dissemination two patients.