Breast cancer is the second leading cause of cancer deaths. This disease is estimated to be diagnosed in over one million people worldwide and to cause more than 400,000 deaths each year. This is a significant health problem in terms of both morbidity and mortality. Chemotherapy forms part of a successful treatment regime in many cases; however, as few as half of the patients treated may benefit from this, as a result of intrinsic or acquired multiple drug resistance (MDR). A range of mechanisms of MDR has been identified using in vitro cell culture models; many, if not all, of which may contribute to breast cancer resistance in the clinical setting. This phenomenon is complicated by the heterogenous nature of breast cancer and the likely multi-factorial nature of clinical resistance. It has been very well established that a "one treatment fits all" approach is not relevant and significant advances have been made through identifying and appropriately treating sub-groups of patients; particularly with newer rationally-targeted therapies, such as the HER2-targeted monoclonal antibody, Trastuzumab, and the dual HER2 and EGFR tyrosine kinase inhibitor, Lapatinab. Furthermore, large defined collaborative studies, using standardised global profiling approaches to study mRNA, microRNAs and proteins, followed by functional genomics studies, by ourselves and others, are underway in order to definitively establish the degree of complexity contributing to drug resistance. The overall vision is to identify the optimum therapeutic regime for individual patients -possibly involving novel targeted therapies, drug resistance modulators, and chemotherapy- to overcome breast cancer.