Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells. As in other cancers, MM plasma cells are thought to be derived from MM-initiating cells, although these remain unidentified. MM patients harbor phenotypic CD19(+) B cells expressing the immunoglobulin gene sequence and the idiotype unique to the individual myeloma clone. Some previous studies have reported that CD19(+) clonotypic B cells can serve as MM-initiating cells. However, we and another group have recently showed that CD19(+) B cells from many MM patients do not reconstitute MM disease upon transplantation into NOD/SCID IL2Rγc(-/-) mice. In the SCID-rab and SCID-hu models, which enable engraftment of human MM in vivo, CD19(-)CD38(++) plasma cells engrafted and rapidly propagated MM, while engraftment of CD19(+) B cells was not detected. Both CD138(-) and CD138(+) plasma cells have the potential to propagate MM clones in vivo in the absence of CD19(+) B cells. Distinct from acute myeloid leukemia-initiating cells, which are derived from undifferentiated stem or progenitor cells, MM-initiating cells are derived from plasma cells, which are terminally differentiated cells. An improved understanding of how the bone marrow microenvironment supports MM-initiating plasma cells, which can initiate MM disease in the SCID-hu (or rab) model, is thus now essential.