Triple-negative breast cancer (TNBC) is the most aggressive subtype of the breast cancer, representing 15-20% of all cases. Due to a lack of clinically available/approved targeted therapies, TNBC patients are still in desperate need of chemotherapy. Although TNBC patients initially have relatively high rates of response to chemotherapy, de novo and acquired resistance constitute a major problem, leading to worsened patient outcomes. Considering the initial high response rates and broad availability and affordability of the chemotherapy agents, it is of great utility to explore the molecular mechanisms driving or contributing to de novo and acquired chemoresistance. Therefore, I developed 9 acquired resistant cell lines and 3 acquired resistant xenografts and harnessed 4 de novo TNBC chemoresistance models to identify the resistance-driving factors for each chemotherapy class/agent. Following characterization of these models in comparison to their parental counterparts at protein level, I determined few candidate proteins involved in chemoresistance. By combining experimental and bioinformatic approaches, I showed translational potential of i) p38 and JNK MAPK, and PI3K/AKT inhibitors, and ER stress inducers in de novo and acquired resistance against antimetabolite chemotherapy agents such as gemcitabine and fluorouracil; ii) dual EGFR/HER2, EGFR, SRC and CDK1 inhibitors against an antimicrotubule agent, paclitaxel; iii) FAK and dual PI3K/mTOR inhibitors against an alkylating chemotherapy agent, cisplatin, and iv) FAK, SRC and PI3K/AKT inhibitors against a topoisomerase II inhibitor, doxorubicin. I further observed that molecular underpinnings of de novo and acquired resistance were largely overlapping albeit not the same. We have also investigated cross chemotherapy resistance patterns in each acquired cell line model, which can guide second- or third-line treatment selection. As a result, I present a rational approach to exploit chemotherapy-small molecule inhibitor combinations for previously untreated or treated TNBC patients. In other words, using low-dose chemotherapy and targeted therapy combinations we provide promising preclinical in vitro data for future in vivo testing.