Metastatic breast cancer is generally considered to be incurable, with response rates and duration of response progressively declining with subsequent lines of treatment. Tumors are either intrinsically resistant to systemic therapy or acquire resistance at some point during multiple courses of therapy. Mechanisms of drug resistance are numerous and include accelerated drug efflux, drug activation and inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. Targeted anticancer agents for the treatment of breast cancer, such as hormonal agents or the more recently approved epidermal growth factor receptor inhibitors, are also associated with intrinsic and acquired resistance. A variety of strategies have been devised to prevent or overcome resistance to systemic anticancer therapy, including drug combinations and sequential regimens. However, it appears that resistance to established cytotoxic and targeted agents is inevitable. Novel agents with reduced susceptibility to resistance may prevent or delay the emergence of resistance and improve survival in patients with common solid tumors, including metastatic breast cancer. We are hopeful that further elucidation of the cellular and molecular processes that allow tumor cells to develop resistance and the use of new agents to combat these mechanisms will improve outcomes for patients with metastatic breast cancer.