Models of tumor initiation and progression. Cancer stem cells may arise through neoplastic changes initiated in normal self-renewing stem cells or downstream progenitors, causing expansion of the stem cell and/or progenitor pool. Secondary events may occur in expanded pools of target cells. Oncogenic events acquired by short-lived progenitors may not persist if self-renewal is not reactivated, as these cells will probably die or undergo terminal differentiation before enough mutations occur for full neoplastic transformation. Tumor progression may be linked to ongoing genetic instability and acquisition of additional changes by cancer stem cells, or possibly by nontumorigenic bulk cells if such changes endow self-renewal. In both cases, evolution of tumor phenotype (including genetic and epigenetic signatures) may be observed.