Cancer stem cells represent a subpopulation of cells within tumor mass, endowed with self-renewal, survival, proliferation, and tumorigenic capacity. These cell populations are potentially associated with cancer prognosis. However, these cells do not play a part in isolation; instead, they are dependent on a variety of signals from their microenvironments. Cancer stem cells have two microenvironment niches: the first one is perivascular niche and the second is hypoxic regions where tumor stem cells locate. Bidirectional signal transduction is found between cancer stem cells and cancer stem cell niches. As a cancer stem cell-specific surface marker, CD133 plays a role in key molecular signaling pathways and high levels of drug-or radiation-resistance. Other molecules closely related to cancer stem cell signaling pathways include Wnt and Hh, which are also associated with cancer drug resistance. Further understanding the molecular mechanisms of pathological basis of cancer stem cells will facilitate the development of new therapeutic targets and new strategies for eradicating cancers. This paper summarizes the molecular mechanisms, and the possibilities and limitations of therapies targeting cancer stem cell.