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A current paradigm shift in cancer research is the realization of extreme heterogeneity of tumor composition in terms of cellular proliferative potential. In the same way that the full hematopoietic system can be reconstituted by a very small number of hematopoietic stem cells administered to an irradiated host, a belief is being established in the field that within a tumor mass there resides a rare cell population with indefinite potential for self-renewal that maintains the tumor mass. The existence of such a population, termed by some as ˵tumor stem cells″ has been postulated by radiobiologists for decades. Currently numerous phenotypic markers and functional properties have been ascribed to tumor stem cells. In multiple myeloma (MM), the question of tumor stem cells becomes even more fascinating since the originating cell is one of the few cells in the body capable of self renewal in non-malignant situations. In this chapter we provide an overview the concept of tumor stem cells, discuss the progress made in MM at understanding tumor stem cells, and propose possible approaches towards therapeutics based on targeting of tumor stem cells. [ABSTRACT FROM AUTHOR]