Multiple myeloma is a clonal B-cell malignancy characterized by aberrant expression of plasma cells within the bone marrow, and is associated with the well known clinical manifestations anemia, bone disease, renal dysfunction, hypercalcemia, and recurrent infections. For many years, melphalan and prednisone represented the standard of care in multiple myeloma therapy, with stem cell transplantation reserved for selected patients. Treatment of the disease has evolved rapidly over the past decade, however, with the development and utilization of thalidomide, lenalidomide, and bortezomib. As a result of these developments, clinical outcomes have improved significantly. This review highlights important historic landmarks as well as more recent events that have played an important role in the evolution of myeloma therapy.