The definition of relapsed and refractory myeloma was straightforward when melphalan-prednisone constituted the mainstay of treatment and high-dose therapy with transplantation was rarely used in myeloma. However, several advances have occurred in the treatment of myeloma over the past decade. Most notably, high-dose therapy and transplantation have become broadly applicable, thalidomide has become available as effective salvage therapy, and several investigational agents with novel mechanisms of action appear to be very promising. Because of the differing properties of some of these agents, it is often possible to control the disease with an alternative treatment approach after the failure of one therapy. Some data indicate that combinations of these agents work when the drugs have failed individually. Therefore, refractory myeloma indicates disease unresponsive to the most recent therapy administered. Broadly, the salvage approaches that are used in patients with refractory or relapsed disease include high-dose dexamethasone, high-dose chemotherapy with autotransplantation, allogeneic hematopoietic stem cell transplantation, thalidomide-based therapies, and novel/investigational agents. The appropriate therapy for a given situation depends on the nature of the disease, age, organ function, bone marrow function, prior treatment, the availability of stem cell donors, and access to novel agents. A therapeutic trial of thalidomide is essential at some stage of the disease in all patients. High-dose therapy with autotransplantation is needed at some stage of the disease in most patients younger than 65 to 70 years.