Chemotherapy remains the mainstay in the treatment of multiple myeloma today. Despite improvements in survival and quality of life that can be attributed to advances in chemotherapeutic treatment, multiple myeloma remains an incurable disease. The development of drug resistance accounts for most treatment failures. Mechanisms of resistance for chemotherapeutic agents occur at the cellular level. Some of these mechanisms are unique for a given individual drug, whereas other mechanisms may confer resistance to a wide variety of agents. Important steps for improving treatment include investigating the resistance mechanisms, developing methods to identify drug-resistant cells, and preventing or circumventing drug resistance once it occurs.