Remaining the most common cancer in women through the 21st century, breast cancer and the development of treatment strategies continue to highlight advances made in our understanding of the pathogenesis of cancer development and resistance to therapies. Despite significant progress in the treatment of breast cancer, resistance to chemotherapeutic agents remains a consistent obstacle in terms of treatment success. Anthracyclines, first used over 30 years ago, and the more recent addition of taxanes to the treatment armamentarium are integral components for both newly diagnosed and recurrent breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer, these agents ultimately become ineffective in controlling disease. With the emergence of a resistant phenotype, tumors are deemed to be drug resistant - frequently multidrug resistant (MDR). A number of processes have been identified that can underlie clinical drug resistance; observations stemming largely from in vitro laboratory-based studies in human cancer cell lines. Recognized mechanisms of resistance include altered expression of the adenosine triphosphate-binding cassette (ABC) superfamily of transporters, alteration in DNA repair pathways, mutations in cellular targets, resistance to initiation of the apoptotic pathway and the development of constitutively activated signaling pathways. As our understanding of mechanisms of resistance expands, the ability to select specific drugs or drug combinations specific to the phenotype of the cancer will become more specific. Illustrative of these advancements are the reported benefits from the use of newer microtubule-Targeting agents in triple negative breast cancer, such as eribulin and ixabepilone; drugs which may be less susceptible to common pathways of drug resistance. Likewise, the combination usage of agents which intersect in receptor crosstalk, such as between the estrogen receptor and the mammalian target of rapamycin (mTOR), have demonstrated synergy in antitumor effects. The recent report of exemestane used in combination with everolimus, have shown great promise in this regard. For patients with HER2 positive disease, a combination approach with trastuzumab and investigational agents such as pertuzumab appear to result in amore complete blockage of HER2 signaling, and improved progression free survival. Thus, as our understanding of the interconnectedness of signaling pathways in breast cancer improves, the ability to rationally design appropriate chemotherapy regimens and delay emerging resistance will improve. © Springer Science+Business Media, LLC 2012.