Several key observations providing evidence for the cancer stem cell hypothesis and insights into the unique biology of these cells have come from the study of multiple myeloma. These include evidence that cancer cells may be functionally heterogeneous in spite of their genetic homogeneity and that malignant progenitors share many biological features with normal adult stem cells including drug resistance and regulatory processes governing self-renewal. We review studies that have examined clonogenic cells in multiple myeloma, highlight controversies regarding the cell of origin in multiple myeloma, and discuss potential targeting strategies.