Multiple myeloma (MM) is a plasma cell malignancy mainly characterized by the accumulation of malignant plasma cells within the bone marrow. This review shows that the biology of CD45 illuminates that of MM and, more specifically, provides a better delineation of a tumor cell 'hierarchy' of clinical interest. We show that in MM, as in normal plasma cell differentiation, there is an intraclonal CD45 hierarchy that is a gradient of CD45 expression on myeloma cells directly related to their proliferation rate and differentiation status. This CD45 hierarchy allows for the design of a cellular model for MM-cell growth and maturation in which CD45 bright myeloma cells represent the proliferating compartment and CD45 low myeloma cells the quiescent compartment. This model includes an aberrant phenotype that is annihilation rather than decline of CD45, annihilation reflecting the terminal phase of the disease and/or an aggressive presentation of MM. Data from the literature suggest that CD45 bright myeloma cells are targeted by interleukin (IL)-6, whereas CD45 negative myeloma cells with a high clonogenic capacity are targeted by insulin/insulin-like growth factor 1 (IGF-1). This model will be useful for both a better understanding of the basic biology of MM and a better stratification of and therapeutic approach to the patients. Finally, this model presents MM as a self-renewing plasma cell disease, although the first oncogenic events such as 14q32 translocations clearly occur earlier in a B cell.