Tumorigenic cancer stem cells [CSCs] are multipotent cells that found together with their nontumorigenic variants in the same clone. Although sharing the same genetic battery, CSCs and their non-tumorigenic progenies respond differently to micro environmental stresses. Thus, hypoxia, inflammation, low pH, shortage in nutrients and cancer therapies result in broad spectrum of changes in signaling pathways. These facts paved the road to a new era in cancer treatment strategies where inhibiting CSCs specific pathways are combined with traditional therapies of bulk tumor cells. Despite the promise such combination brought to cancer cure improvement, resistance to some to some CSCs-related therapies is noticed. Thus, this review focuses on the mechanisms that may involve in such resistance including drug efflux by ABC transporters, activation of aldehyde dehydrogenase and developmental pathways, enhanced DNAdamage response and autophagy and microenvironmental conditions. This review discusses as well the possible therapeutic strategies for improving cancer treatment.