Treatment options for patients with relapsed myeloma are a rapidly moving entity. Although autologous transplantation has improved outcomes for younger patients, the use of a second autologous transplant in the relapsed setting has less benefit. Nonmyeloablative allogeneic transplant is being studied in several large cooperative group trials, but to date early auto/mini-allo does not appear to be superior to tandem autologous transplantation. The greatest benefit in the relapsed setting has been demonstrated using novel targeted agents with biologically based therapies. The response rates from thalidomide with and without dexamethasone, bortezomib, and lenalidomide with and without dexamethasone clearly demonstrate high levels of activity with encouraging durations of remission. More recent studies are combining novel agents, and small phase I/II trials are demonstrating higher overall response and complete remission rates. The next generation of novel agents targeting heat shock proteins, the mitogen-activated protein kinase pathway, and monoclonal antibodies are further expanding the list of future potential agents. The rapid clinical development of targeting agents will give us more options to treat patients with relapsed or refractory myeloma, thereby improving quality of life and overall survival.