Cancer stem cell (CSC) derive from normal adult mutated stem cell, which are a small sub-population of cells within tumors, having self-renewal capacity, pluripotency as well as tumor initiating capability and being responsible for tumor maintenance, metastasis, relapse and chemo-radiotherapy resistance. Surgery, chemotherapy and radiotherapy are the common treatment options against different types of cancer, however, cancer cells except CSCs could be eradicated by conventional therapies. Thus, CSCs is the main culprit in cancer pathogenesis, therefore, eradication of CSCs by the novel therapeutic strategies is imperative for better management of patients with cancers. Hence, in this chapter, we explain different types of novel therapeutic strategies such as immunotherapy, gene therapy, epigenetic therapy, natural products, metabolism based therapeutic strategies for the elimination of CSC, thereby could improving the clinical outcome of patients with cancers.