Multiple myeloma is a malignant disease characterized by plasmacytosis, paraprotein production, bone lesions, hypercalcemia, susceptibility to infections, and renal impairment. The underlying pathophysiologic phenomena of the clinical features include suppression of humoral- and cell-mediated immunity, elevation of IL-6, abnormalities of the bone marrow microenvironment, and increased osteoclastic activity. Overwhelming predictors of prognosis include albumin, beta2-microglobulin, and chromosomal karyotype. With modern, intensive therapy including autologous hematopoietic stem cell transplantation, the median survival is approximately 5 yr. The disease is incurable and eventually relapses; requiring salvage therapy. The development of newer agents such as thalidomide, bortezomib, and lenalidomide--drugs that interfere with several of the complex pathophysiologic steps--has improved the outlook of relapsed disease significantly. Current studies are directed at exploring the use of these novel agents earlier in the course of therapy, development of newer targeted therapies, and the use of gene expression profiling to individualize therapy.