Normal stem cell self-renewal is tightly regulated, in part, by intrinsic transcription factor-based pathways that integrate extrinsic growth factor signals. During tumorigenesis, deregulated transcription factor expression or activation can promote abnormal self-renewal, proliferation, and differentiation of neoplastic cells. Increasing evidence indicates that a subset of cells within a tumor has these stem cell-like characteristics, and that these cancer stem cells drive tumor progression. Chromosomal translocations and point mutations in transcription factor genes encoding oncogenes, such as c-Myc, and tumor suppressors, including p53, are commonly associated with cancer stem cells. Additional understanding of the transcription factor programs that regulate normal stem cell self-renewal will provide more avenues for targeting and eliminating cancer stem cells.