Stem cells are unique cells that can self-renew and differentiate into many cell types. Plasticity is a fundamental characteristic of stem cells and it is regulated by reversible epigenetic modifications. Although gene-restriction programs are established during embryonic development when cell lineages are formed, stem cells retain a degree of flexibility that is essential for tissue regeneration. For instance, quiescent adult stem cells can be induced to proliferate and trans-differentiate in response to injury. The same degree of plasticity is observed in cancer, where cancer cells with stem cell characteristics (or cancer stem cells) are formed by transformation of normal stem cells or de-differentiation of somatic cells. Reprogramming experiments with normal somatic cells and cancer cells show that epigenetic landscapes are more plastic than originally thought and that their manipulation can induce changes in cell fate. Our knowledge of stem cell function is still limited and only by understanding the mechanisms regulating developmental potential together with the definition of epigenetic maps of normal and diseased tissues we can reveal the true extent of their plasticity. In return, the control of plastic epigenetic programs in stem cells will allow us to develop effective treatments for degenerative diseases and cancer.