Metastasis of primary cancer to the brain is a leading cause of all cancer related deaths, with a prevalence of approximately 40% and a median survival of nine months if an aggressive treatment regime is implemented. The etiology and underpinning molecular mechanisms of brain metastasis is not well understood, although recent research has implicated the Wnt/TCF4 and the HER/EGFR pathways in lung and breast cancer metastases respectively. The present study investigated the genomic landscape of brain metastases from 30 patients (with matched normal blood samples) which originated from a range of primary tumour sites (5 breast cancer; 6 melanoma; 16 lung cancer; one oesophageal cancer; two metastases of unknown origin) utilizing both Illumina HumanOmni 2.5-8 v1 SNP arrays and Illumina HiSeq Exome sequencing (TargetSEQ exome capture including VEGA, RefSEQ, CCDS and miRNA targets). Cellularity was measured using the qPure tool, with an average tumour cellularity of 78%. Copy number events were determined from the SNP arrays using the GAP and GenoCN tools. The samples were sequenced to an average per base pair coverage ranging from 52 to 118, and 80% of targets were covered at 21-75 fold. Somatic substitutions and indels were identified using qSNP and Pindel, and verification was performed by comparison to SOLiD 5500 (ABI) sequencing of a subset of sample variants. Key biological pathways were investigated using Ingenuity Pathway Analysis software. Particular attention was paid to the NRG-HER3 axis, which has been shown to be upregulated in breast metastases relevant to matched primary breast tumours. Of note, NRG1 had a loss of copy number in 11 of 30 brain metastases samples. It is envisaged that the current work may provide important biological insights into the genomic characterization and evolution of brain metastases and additionally identify druggable targets of clinical relevance.