Breast cancer has remained a serious health concern globally for women despite the healthcare advances which have enabled early diagnosis and treatment. Due to its metastatic ability and development of resistance to chemotherapies, triple-negative breast cancer is an extremely challenging subtype to treat. Targeted and optimized therapy is imperative as these tumors have higher recurrence rates than other types of breast cancers. This review is focused on the novel therapeutic strategies that have been proposed for the treatment of these aggressive cancers including alternative approaches like patient selection using biomarkers, metabolic reprogramming and development of smart drug delivery systems (SDDS) using targeted nanoparticles to treat the tumors as well as ensure prevention of recurrence. All of these approaches are aimed towards removing and treating the malignancies of triple-negative breast cancer (TNBC) and optimizing the therapies according to the patient cohorts. Further research is, however, necessary for the designing of an effective therapeutic regimen for patient sub-groups suffering from TNBC. © 2023, Hacettepe University, Faculty of Pharmacy. All rights reserved.