Each year, more than 1.6 million people in the USA are diagnosed with new cancers, and this number has been continuously increasing for decades. Most of the targeted therapeutics tested thus far have shown little or limited sustained survival benefit. The failure to achieve a cure may include the presence of self-renewing, highly tumorigenic cancer stem cells (CSCs) contributing to therapeutic resistance and invasion into normal tissues. Targeting CSCs is probably mandated to inhibit tumor growth and sensitize tumors to conventional therapies. In a tumor mass, however, CSCs are tightly associated with other cells including non-CSCs and stromal cells. Nonetheless, molecular mechanisms for the intercellular communication remain largely elusive. Recent studies in both mammalian and nonmammalian system have raised a possible novel concept that cellular competition between CSCs and non-CSCs may induce engulfment of non-CSCs by CSCs. The ultimate goals of CSC-directed medical research include the establishment of a new concept of intercellular competition within tumors to better clarify the mechanism of tumor heterogeneity and targeted therapies for molecules responsible for a gain of resistance to current therapies. This concept, if proven true, would challenge the current research and clinical practice hurdles, thereby creating a firm path to development of a novel strategy to target the newly identified cellular alterations in cancers.