- A prominent model of tumor progression posits that normal self-renewing and multipotent stem cells are the initial target of transformation. This view has been robustly challenged by the recurring observation that transit-amplifying cells and differentiated progenitors can initiate neoplasia outside the stem cell zone thus qualifying as cancer cells- of -origin. The emerging concept is that a cancer stem cell and a cancer cell-of-origin are not necessarily the same cell. Importantly, progenitor cells were shown to possess remarkable plasticity and to revert, on demand, to a stem cell like-state.The present review revisits our early hypothesis that colonic progenitors acquiring a mutant adenomatous polyposis coli gene after exiting the stem zone may serve as genuine cancer cells -of- origin. New findings consonant with this view are examined, and tenable molecular and cellular mechanisms underpinning the plasticity of progenitor cells in the gastrointestinal tract and in other tissues are discussed. The translational impact of cell plasticity is addressed, and recommendations for future research are advanced. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.