Systemic therapy improves disease-free survival in patients with breast cancer, but does not cure patients with advanced or metastatic disease, and fails to benefit the majority of patients with localized breast cancer. Intrinsic resistance to chemotherapy is emerging as a significant cause of treatment failure and evolving research has identified several potential causes of resistance, such as drug efflux pumps, disregulation of apoptosis and cancer stem cells. Building upon preclinical models, drugs designed to reverse resistance to therapy are currently under investigation in clinical trials for the treatment of breast cancer.