Multiple myeloma (MM) is a neoplasm of post–germinal center, terminally differentiated B cells. It is characterized by a multifocal proliferation of clonal, long-lived plasma cells within the bone marrow (BM) and associated skeletal destruction, serum monoclonal gammopathy, immune suppression, and end-organ sequelae. MM is preceded by an age-progressive premalignant condition termed monoclonal gammopathy of undetermined significance. Unlike the genomes of most hematological malignancies, and similar to those of solid-tissue neoplasms, MM genomes are typified by numerous structural and numerical chromosomal aberrations as well as mutations in a number of oncogenes and tumor-suppressor genes, some of which have been linked to disease pathogenesis and clinical behavior. Recent studies have also defined the importance of interactions between the MM cells and their BM microenvironment, dysregulation in signaling pathways and in a specialized subpopulation of cells within the tumor (termed myeloma cancer stem cells) for tumor cell growth and survival, and the development of resistance to therapy.