ABSTRACT: Breast cancer has become one of the biggest concerns for oncologists in the past few decades because of its unpredictable etiopathology and nonavailability of personalized translational medicine. The number of women getting affected by breast cancer has increased dramatically, owing to lifestyle and environmental changes. Besides, the development of multidrug resistance has become a challenge in the therapeutic management of breast cancer. Studies reveal that the use of monotherapy is not effective in the management of breast cancer due to high toxicity and the development of resistance. Combination therapies, such as radiation therapy with adjuvant therapy, endocrine therapy with chemotherapy, and targeted therapy with immunotherapy, are found to be effective. Thus, multimodal and combination treatments, along with nanomedicine, have emerged as a promising strategy with minimum side effects and drug resistance. In this review, we emphasize the multimodal approaches and recent advancements in breast cancer treatment modalities, giving importance to the current data on clinical trials. The novel treatment approach by targeted therapy, according to type, such as luminal, HER2 positive, and triple-negative breast cancer, are discussed. Further, passive and active targeting technologies, including nanoparticles, bioconjugate systems, stimuli-responsive, and nucleic acid delivery systems, including siRNA and aptamer, are explained. The recent research exploring the role of nanomedicine in combination therapy and the possible use of artificial intelligence in breast cancer therapy is also discussed herein. The complexity and dynamism of disease changes require the constant upgrading of knowledge, and innovation is essential for future drug development for treating breast cancer.