Abstract: Triple-Negative Breast Cancer (TNBC) accounts for approximately one-fifth of breast cancer incidence but disproportionately high mortality. Two-thirds of early-stage TNBCs are resistant to pre-surgical chemotherapy and highly prone to relapse within 3 years. Morever, no advanced therapies are indicated for patients with these cancers. We have embarked on a comprehensive genomic analysis of chemoresistant TNBC to gain an in-depth understanding of molecular entities driving chemoresistance and relapse. By collecting somatic mutation and copy number, RNA-sequencing, and outcome data in the context of a phase II post-neoadjuvant clinical trial, we have uncovered several molecular mechanisms behind these aggressive cancers. Through the analysis of matched pairs sampled before and after chemotherapy, we have discovered multiple means by which tumors are able to overcome the effects of chemotherapy including clonal evolution of high-level oncogene amplification, repression of the in situ immune system, and upregulation of the stem cell-related MEK-ERK and JAK-STAT pathways. Investigation into factors related to prognosis revealed important correlations between relapse and immune and JAK-STAT signaling. Finally, using a novel method of demarcating loss-of-function of p53, which we have termed graduated inactivation, we discovered additional associations between p53 loss and relapse, mortality, and MYC signalling.