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Stem cells continue to attract considerable attention and provide hope for the development of new cell-based therapies for degenerative diseases. Unlocking the full therapeutic potential of stem cells requires an understanding of the mechanisms by which they are generated, self-renew, and differentiate. The application of post-genomic technologies is beginning to provide insight into the nature of the molecular ground state of different stem cell compartments. One emerging theme is the considerable molecular complexity in which many possible differentiation pathways are primed, providing one possible strategy for enabling the diverse responsiveness of stem cells. This new information should ultimately reveal any common molecular attributes of “stemness” and aid in rational approaches to the manipulation of stem cells for therapeutic benefit.