Management of refractory myeloma represents a common and challenging clinical problem. Approximately 30% to 50% of patients with multiple myeloma do not respond to first-line therapy, and those who initially achieve a remission will eventually relapse. Surprisingly, there is no routinely accepted approach to patients with refractory disease. Therefore, we review the literature in an attempt to provide an overview of the published results and outline our treatment recommendations for such patients. We suggest the following: (1) for truly resistant patients (ie, those who clearly progress with initial therapy), administration of high-dose or pulsed glucocorticosteroids is the best treatment, with an expected response of 40% (defined as a greater than or equal to 50% reduction in monoclonal [M]-protein concentration); (2) for patients who relapse during therapy or relapse within 6 months of stopping the initial treatment, the VAD regimen (vincristine, doxorubicin, and dexamethasone) is one of the most effective salvage therapies, resulting in an approximately 75% response rate (greater than or equal to 50% reduction in M-protein concentration); (3) for patients who relapse within more than 6 months of stopping therapy (unmaintained remission), reinitiation of the initial therapy represents an excellent alternative, leading to recontrol in 60% to 70% of patients (greater than or equal to 50% reduction in M-protein concentration). If progression is observed or if there is response and then relapse in this setting, VAD chemotherapy can be administered again. (4) Patients who fail second-line salvage therapies should enter well-designed clinical trials to evaluate new treatment modalities. If this is not feasible, alpha-interferon or "systemic" radiotherapy are recommended in selected cases.