Embryonic, adult and cancer stem cells are all defined by their functional ability to self-renew and differentiate. During an immune response, memory B cells share this capacity as they can divide to generate daughter memory B cells or differentiate into antibody secreting plasma cells. We hypothesize that the same pathways and programs that regulate stem cell fate specification may also control B cell fate decisions. Further, we believe that studying the mechanisms that control normal memory B cell development will provide insight into the aberrancies that drive cancer stem cells. Here we demonstrate that during B cell maturation, classic stem cell programs may be induced, including telomerase activation. We also show that human B cells can be induced to differentiate in vitro by CpG ODN stimulation. Applying these findings to malignant cells, we determined that we could induce multiple myeloma cancer stem cell differentiation by inhibiting telomerase, and we could drive mantle cell lymphoma cancer stem cell differentiation using CpG ODN. We propose that by understanding the mechanisms that regulate normal development, targeted therapies can be discovered to inhibit cancer stem cell self-renewal and malignant differentiation in a wide range of tumor types.