The post-TCGA (The Cancer Genome Atlas) landscape for high-grade serous ovarian carcinoma is marked by surprisingly few recurrent somatic mutations. Instead, this disease exhibits a complex genomic terrain marked by copy number alterations that are so widespread that few other cancer types mirror its complexity. The challenge now is to elucidate the alterations that are key players in tumorigenesis, tumor viability and chemotherapy resistance. Although mutations in the BRCA genes account for ~20% of all HGSCs, dysfunction in the BRCA network and homologous recombination appears to be more widespread. Intriguingly, BRCA mutations and Cyclin E (CCNE1) amplifications are mutually exclusive, yet both BRCA1/2 dysfunction and CCNE1 amplification lead to wide-spread genomic instability and tumor progression. PARP inhibition has been shown to be synthetically lethal with BRCA1, while CCNE1 amplification is associated with primary treatment failure and poor outcome. We are now deploying next generation sequencing techniques (WES, RNA Seq, ATAC-Seq) to characterize the ‘omic’ alterations in early precursors of BRCA1/2 mutant and CCNE1 amplified high-grade serous ovarian carcinomas. We are integrating these findings into our in vitro and in vivo platforms to perform whole genome screens with the goal of identifying vulnerabilities that may lead to new therapeutic interventions.