Multiple Myeloma (MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome. Although the plasma cell is the predominant cell type in MM, several studies have shown that less mature B cells, which are clonally related to the malignant plasma cells, are present in the bone marrow and peripheral blood of MM patients. The significance of these so-called myeloma clonotypic B cells in the disease process remains largely unknown. In this review the role of myeloma clonotypic B cells and myeloma tumor clone heterogeneity in relation to prognosis and clinical outcome are discussed.