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Simple Summary: We find that mutations in the TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 genes are associated with prostate cancer metastasis and mutations in EYA1 and CSMD3 are associated with poor outcome. Our finding that oxidative phosphorylation is associated with metastasis and identification of mutations enriched in prostate cancer metastases have implications for our understanding of the molecular events required for prostate metastasis. They also have relevance for our understanding of prostate cancer health disparities and provide a rationale for identification of compounds that target oxidative phosphorylation in metastatic prostate cancer. Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer. [ABSTRACT FROM AUTHOR]