Since the discovery of specific populations of cells with stem-like characteristics in human leukemias, phenotypically and/or functionally similar tumor-promoting cells have been identified in a variety of human cancers. By dint of the similarities to normal human stem cells in terms of self-renewal, differentiation, long life span, and proliferative capacity, these defined populations of cells within the bulk tumor are referred to as "cancer stem cells (CSCs)". The presence of CSCs has challenged the age-old dogma of carcinogenesis, which posits that all cells within a tissue retain the capacity to generate tumors. With respect to the frequency of CSCs, there is still a lack of consensus as in some recent models the notion that these cells constitute a very small proportion within the tumor has been challenged. Another issue that remains unresolved is the existence of a "global" marker, although reference has been made to the CD133(+), CD34(+)CD38(-), and CD44(+)CD24(-) populations as the functional stem-like cells in different cancers. Nevertheless, the identification of this sub-set within the bulk tumor and its contribution to chemotherapy resistance suggest that the CSCs could be the Achilles heel in terms of chemosensitization. Therefore, a paradigm is emerging that an effective therapeutic approach against cancers is to target this critical pool of cells that have the capacity to self-renew and proliferate as well as evade death signals. Here we provide a brief review of the literature vis a vis the various mechanisms of defective apoptotic signaling in CSCs with potential for therapeutic intervention.